Vinyl phenyl derivatives as GLK activators

ABSTRACT

The invention relates to novel compounds of Formula (I) or a salt, solvate or prodrug thereof, wherein A, R 1 , R 2 , R 3 , n and m are described in the specification, useful in the treatment of 
     
       
         
         
             
             
         
       
     
     a disease or condition mediated through glucokinase (GLK), such as type 2 diabetes. The invention also relates to methods for preparing compounds of Formula (I) and their use as medicaments in the treatment of diseases mediated by glucokinase.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB02/02903, filed Jun. 24, 2002, whichclaims priority from Sweden Patent Application No. 0102299-5, filed Jun.26, 2001 the specifications of which are incorporated by referenceherein. International Application No. PCT/GB02/02903 was published underPCT Article 21 (2) in English.

FIELD OF THE INVENTION

The present invention relates to compounds which activate glucokinase(GLK), leading to a decreased glucose threshold for insulin secretion.In addition the compounds are predicted to lower blood glucose byincreasing hepatic glucose uptake. Such compounds may have utility inthe treatment of Type 2 diabetes and obesity. The invention also relatesto pharmaceutical compositions comprising a compound of the invention,and use of such a compound in the conditions described above.

In the pancreatic β-cell and liver parenchymal cells the main plasmamembrane glucose transporter is GLUT2. Under physiological glucoseconcentrations the rate at which GLUT2 transports glucose across themembrane is not rate limiting to the overall rate of glucose uptake inthese cells. The rate of glucose uptake is limited by the rate ofphosphorylation of glucose to glucose-6-phosphate (G-6-P) which iscatalysed by glucokinase (GLK) [1]. GLK has a high (6–10 mM) Km forglucose and is not inhibited by physiological concentrations of G-6-P[1]. GLK expression is limited to a few tissues and cell types, mostnotably pancreatic β-cells and liver cells (hepatocytes) [1]. In thesecells GLK activity is rate limiting for glucose utilisation andtherefore regulates the extent of glucose induced insulin secretion andhepatic glycogen synthesis. These processes are critical in themaintenance of whole body glucose homeostasis and both are dysfunctionalin diabetes [2].

In one sub-type of diabetes, Type 2 maturity-onset diabetes of the young(MODY-2), the diabetes is caused by GLK loss of function mutations [3,4]. Hyperglycaemia in MODY-2 patients results from defective glucoseutilisation in both the pancreas and liver [5]. Defective glucoseutilisation in the pancreas of MODY-2 patients results in a raisedthreshold for glucose stimulated insulin secretion. Conversely, rareactivating mutations of GLK reduce this threshold resulting in familialhyperinsulinism [6, 7]. In addition to the reduced GLK activity observedin MODY-2 diabetics, hepatic glucokinase activity is also decreased intype 2 diabetics [8]. Importantly, global or liver selectiveoverexpression of GLK prevents or reverses the development of thediabetic phenotype in both dietary and genetic models of the disease[9–12]. Moreover, acute treatment of type 2 diabetics with fructoseimproves glucose tolerance through stimulation of hepatic glucoseutilisation [13]. This effect is believed to be mediated through afructose induced increase in cytosolic GLK activity in the hepatocyte bythe mechanism described below [13].

Hepatic GLK activity is inhibited through association with GLKregulatory protein (GLKRP). The GLK/GLKRP complex is stabilised byfructose-6-phosphate (F6P) binding to the GLKRP and destabilised bydisplacement of this sugar phosphate by fructose-1-phosphate (F1P). F1Pis generated by fructokinase mediated phosphorylation of dietaryfructose. Consequently, GLK/GLKRP complex integrity and hepatic GLKactivity is regulated in a nutritionally dependent manner as F6P iselevated in the post-absorptive state whereas F1P predominates in thepost-prandial state. In contrast to the hepatocyte, the pancreaticβ-cell expresses GLK in the absence of GLKRP. Therefore, β- cell GLKactivity is regulated exclusively by the availability of its substrate,glucose. Small molecules may activate GLK either directly or throughdestabilising the GLK/GLKRP complex. The former class of compounds arepredicted to stimulate glucose utilisation in both the liver and thepancreas whereas the latter are predicted to act exclusively in theliver. However, compounds with either profile are predicted to be oftherapeutic benefit in treating Type 2 diabetes as this disease ischaracterised by defective glucose utilisation in both tissues.

In WO0058293 and WO 01/44216 (Roche), a series of benzylcarbamoylcompounds are described as glucokinase activators. The mechanism bywhich such compounds activate GLK is assessed by measuring the directeffect of such compounds in an assay in which GLK activity is linked toNADH production, which in turn is measured optically—see details of thein vitro assay described in Example A.

In WO9622282/93/94/95 and WO9749707/8 are disclosed a number ofintermediates used in the preparation of compounds useful as vasopressinagents which are related to those disclosed in the present invention.Related compounds are also disclosed in WO9641795 and JP8143565(vasopressin antagonism), in JP8301760 (skin damage prevention) and inEP619116 (osetopathy).

We present as a feature of the invention the use of a compound ofFormula (I) or a salt, pro-drug or solvate thereof, in the preparationof a medicament for use in the treatment or prevention of a disease ormedical condition mediated through GLK:

wherein

-   -   A is heteroaryl;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3 or 4;    -   and n+m>0;    -   each R¹ is independently selected from OH, —(CH₂)₁₋₄OH,        —CH_(3-a)F_(a), —(CH₂)₁₋₄CH_(3-a)F_(a), —OCH_(3-a)F_(a), halo,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, NO₂, NH₂, —NH-C₁₋₄alkyl,        —N—di—(C₁₋₄alkyl), CN, formyl, phenyl or heterocyclyl optionally        substituted by C₁₋₆alkyl;    -   each R² is the group Y—X—        -   wherein each X is a linker independently selected from:            -   —Z—, —O—Z—, —O—Z—O—Z—, —C(O)O—Z—, —OC(O)—Z—, —S—Z—,                —SO—Z—, —SO₂—Z—, —N(R⁷)—Z—, —N(R⁷)SO₂—Z—, —SO₂N(R⁷)—Z—,                —(CH₂)₁₋₄—, —CH═CH—Z—, —C≡C—Z—, —N(R⁷)CO—Z—,                —CON(R⁷)—Z—, —C(O)N(R⁷)S(O)₂—Z—, —S(O)₂N(R⁷)C(O)—Z—,                —C(O)—Z— or a direct bond;        -   each Z is independently a direct bond, C₂₋₆alkenylene or a            group of the formula —(CH₂)_(p)—C(R⁷)₂—(CH₂)_(q)—;        -   each Y is independently selected from aryl-Z¹—,            heterocyclyl-Z¹—, C₃₋₇cycloalkyl-Z¹—, C₁₋₆alkyl ,            C₂₋₆alkenyl, C₂₋₆alkynyl, —(CH₂)₁₋₄CH_(3-a)F_(a) or            —CH(OH)CH_(3-a)F_(a); wherein each Y is independently            optionally substituted by up to 3 R⁴ groups;            -   each R⁴ is independently selected from halo,                —CH_(3-a)F_(a), CN, NO₂, NH₂, C₁₋₆alkyl, —OC₁₋₆alkyl,                —COOH, —C(O)OC₁₋₆alkyl, OH or phenyl optionally                substituted by C₁₋₆alkyl or —C(O)OC₁₋₆alkyl, or R⁵—X¹—,                where X¹ is independently as defined in X above and R⁵                is selected from hydrogen, C₁₋₆alkyl, —CH_(3-a)F_(a);                phenyl, naphthyl, heterocyclyl or C₃₋₇cycloalkyl; and R⁵                is optionally substituted by halo, C₁₋₆alkyl,                —CH_(3-a)F_(a); CN, NO₂, NH₂, COOH, or —C(O)OC₁₋₆alkyl,                -   wherein each phenyl, naphthyl or heterocyclyl ring                    in R⁵ is optionally substituted by halo,                    CH_(3-a)F_(a), CN, NO₂, NH₂, C₁₋₆alkyl, —OC₁₋₆alkyl,                    COOH, —C(O)OC₁₋₆alkyl or OH;            -   each Z¹ is independently a direct bond, C₂₋₆alkenylene                or a group of the formula —(CH₂)_(p)—C(R⁶)₂—(CH₂)_(q)—;    -   R³ is selected from OH, —O-C₁₋₆alkyl or NHR⁶;    -   R⁶ is selected from hydrogen, C₁₋₆alkyl, —O-C₁₋₆alkyl,        —SO₂C₁₋₆alkyl, —(CH₂)₀₋₃OH;    -   R⁷ is independently selected from hydrogen, C₁₋₆alkyl or        —C₂₋₄alkyl-O-C₁₋₄alkyl;    -   each a is independently 1, 2 or 3;    -   p is an integer between 0 and 2;    -   q is an integer between 0 and 2;    -   and p+q<4.

According to a further feature of the invention there is provided theuse of a compound of Formula (Ia) or a salt, pro-drug or solvatethereof, in the preparation of a medicament for use n the treatment orprevention of a disease or medical condition mediated through GLK:

wherein

-   -   m is 0, 1 or 2;    -   n is 0, 1, 2, 3 or 4;    -   and n+m>0;    -   each R¹ is independently selected from OH, (CH₂)₁₋₄OH,        CH_(3-a)F_(a), (CH₂)₁₋₄CH_(3-a)F_(a, OCH) _(3-a)F_(a), halo,        C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, NO₂, NH₂, CN, phenyl or a        heterocyclyl optionally substituted by C₁₋₆alkyl;    -   each R² is the group Y—X—        -   wherein each X is a linker independently selected from            —O(CH₂)₀₋₃—, —(CH₂)₀₋₃O—, —C(O)O(CH₂)₀₋₃—, —S(CH₂)₀₋₃—,            —SO(CH₂)₀₋₃—, —SO₂(CH₂)₀₋₃—, —NHSO₂, —SO₂NH—, —(CH₂)₁₋₄—,            —CH═CH(CH₂)₀₋₂—, —C≡C(CH₂)₀₋₂—, —NHCO—, —CONH—;        -   each Y is independently selected from phenyl(CH₂)₀₋₂,            naphthyl(CH₂)₀₋₂, heterocyclyl(CH₂)₀₋₂, C₃₋₇            cycloalkyl(CH₂)₀₋₂, C₁₋₆ alkyl, OC₁₋₆alkyl, C₂₋₆ alkenyl,            C₂₋₆ alkynyl, or CH(OH)CH_(3-a)F_(a); wherein each Y is            independently optionally substituted by one or more R⁴            groups;            -   each R⁴ is independently selected from halo,                CH_(3-a)F_(a), OCH_(3-a)F_(a), CN, NO₂, NH₂, C₁₋₆alkyl,                OC₁₋₆alkyl, COOH, (CH₂)₀₋₃COOH, O(CH₂)₀₋₃COOH,                C(O)OC₁₋₆alkyl, C₁₋₆alkyl, C₁₋₆alkyl(O)OC₁₋₆alkyl,                CO-phenyl, CONH₂, CONH-phenyl, SO₂NH₂, SO₂C₁₋₆alkyl, OH,                or phenyl optionally substituted by one or more R⁵                groups where R⁵ is selected from hydrogen, C₁₋₆alkyl or                C(O)OC₁₋₆alkyl.    -   each a is independently 1, 2 or 3;    -   R³ is selected from hydrogen, C₁₋₆alkyl or NHR⁶;    -   R⁶ is selected from hydrogen, C₁₋₆alkyl, OC₁₋₆alkyl,        SO₂C₁₋₆alkyl, (CH₂)₀₋₃OH.

According to a further feature of the invention there is provide acompound of Formula (Ib) or a salt, solvate or pro-drug thereof;

wherein

-   -   A is heteroaryl;    -   m is 0, 1 or 2;    -   n is 0, 1, 2, 3 or 4;    -   and n+m>0;    -   each R¹ is independently selected from OH, —(CH₂)₁₋₄OH,        —CH_(3-a)F_(a), —(CH₂)₁₋₄CH_(3-a)F_(a), —OCH_(3-a)F_(a), halo,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, NO₂, NH₂, —NH-C₁₋₄alkyl,        —N-di-(C₁₋₄alkyl), CN, formyl, phenyl or heterocyclyl optionally        substituted by C₁₋₆alkyl;    -   each R² is the group Y—X—        -   wherein each X is a linker independently selected from:            -   —Z—, —O—Z—, —O—Z—O—Z—, —C(O)O—Z—, —OC(O)—Z—, —S—Z—,                —SO—Z—, —SO₂—Z—, —N(R⁷)—Z—, —N(R⁷)SO₂—Z—, —SO₂N(R⁷)—Z—,                —(CH₂)₁₋₄—, —CH═CH—Z—, —C≡C—Z—, —N(R⁷)CO—Z—,                —CON(R⁷)—Z—, —C(O)N(R⁷)S(O)₂—Z—, —S(O)₂N(R⁷)C(O)—Z—,                —C(O)—Z— or a direct bond;    -   each Z is independently a direct bond, C₂₋₆alkenylene or a group        of the formula —(CH₂)_(p)—C(R⁷)₂—(CH₂)_(q)—;    -   each Y is independently selected from aryl-Z¹—,        heterocyclyl-Z¹—, C₃₋₇cycloalkyl-Z¹—, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, —(CH₂)₁₋₄CH_(3-a)F_(a) or —CH(OH)CH_(3-a)F_(a);        wherein each Y is independently optionally substituted by up to        3 R⁴ groups;        -   each R⁴ is independently selected from halo, —CH_(3-a)F_(a),            CN, NO₂, NH₂, C₁₋₆alkyl, —OC₁₋₆alkyl, —COOH,            —C(O)OC₁₋₆alkyl, OH or phenyl optionally substituted by            C₁₋₆alkyl or —C(O)OC₁₋₆alkyl, or R⁵—X¹—, where X¹ is            independently as defined in X above and R⁵ is selected from            hydrogen, C₁₋₆alkyl, —CH_(3-a)F_(a), phenyl, naphthyl,            heterocyclyl or C₃₋₇cycloalkyl; and R⁵ is optionally            substituted by halo, C₁₋₆alkyl, —CH_(3-a)F_(a), CN, NO₂,            NH₂, COOH, or —C(O)OC₁₋₆alkyl,            -   wherein each phenyl, naphthyl or heterocyclyl ring in R⁵                is optionally substituted by halo, CH_(3-a)F_(a), CN,                NO₂, NH₂, C₁₋₆alkyl, —OC₁₋₆alkyl, COOH, —C(O)OC₁₋₆alkyl                or OH;    -   each Z¹ is independently a direct bond, C₂₋₆alkenylene or a        group of the formula —(CH₂)_(p)—C(R⁶)₂—(CH₂)_(q)—;    -   R³ is selected from OH, —O-C₁₋₆alkyl or NHR⁶;    -   R⁶ is selected from hydrogen, C₁₋₆alkyl, —O—C₁₋₆alkyl,        —SO₂C₁₋₆alkyl, —(CH₂)₀₋₃OH;    -   R⁷ is independently selected from hydrogen, C₁₋₆alkyl or        —C₂₋₄alkyl-O-C₁₋₄alkyl;    -   each a is independently 1, 2 or 3;    -   p is an integer between 0 and 2;    -   q is an integer between 0 and 2;    -   and p+q<4;

-   with the proviso that:

-   (i) where m is 1 or 2 and n is 0, R³ is OH or —O-C₁₋₆alkyl, then R¹    is other than OH, CN, halo, methyl, amino or nitro;

-   (ii) when m=0, n=1, X is —O—, —O—C(O)—, —S—, —S(O)—, —S(O₂)—,    —N(CH₃)—, —N(CH₃)—CH₂— or —C(O)—NH—, R³ is OH or —O-C₁₋₆alkyl, then    Y cannot be C₁₋₆alkyl or C₁₋₆alkyl substituted by C₁₋₆alkyl;

-   (iii) when m is 0 or m is 1 and R¹ is NO₂, R³ is OH or —O-C₁₋₆alkyl,    then when n is 2 (R²)_(n) cannot be di-C₁₋₆alkyl-O— or C₁₋₆alkyl-O—    C₁₋₆alkenyl-O— and when n is 3 (R²)_(n) cannot be tri-C₁₋₆alkyl-O—;

-   (iv) when A is pyridyl, m is 0 or m is 1 and R¹ is halo, n is 1 and    R² is phenyl, phenyl-CH₂—O— or pyridyl-NH—, then R³ cannot be OH or    —O-C₁₋₆alkyl; and

-   (v) when A is pyridyl, R³ is OH, m is 0, n is 2 and one of the R²    groups is phenyl-CH₂—O—, then the other R² group must be other than    CH₃—S— or CH₃—SO₂—.

According to a further feature of the invention there is provided acompound of Formula (Ib) or salt, solvate of pro-drug thereof,

-   wherein A is pyridyl-   with the proviso that-   (i) when m is 1 or 2 and n is 0 then R¹ is other than halo, methyl,    amino or nitro;-   (ii) when m=0, n=1, X is —O—, —S—, —S(O)—, —S(O₂)—, —N(CH₃)—, or    —N(CH₃)—CH₂—, R³ is OH or —O-C₁₋₆alkyl, then Y cannot be methyl;-   (iii) when R³ is OH, m is 0, n is 2 and one of the R² groups is    phenyl —CH₂—O—, then the other R² group must be other than CH₃—S— or    CH₃—SO₂—; and-   (iv) when m is 0 or m is 1 and R¹ is halo, n is 1 and R² is phenyl,    phenyl-CH₂—O— or pyridyl-NH—, then R³ cannot be OH or —O-C₁₋₆alkyl;

According to a further feature of the invention there is provided acompound of Formula (Ic) or a salt, solvate or pro-drug thereof;

wherein

-   -   m is 0, 1 or 2;    -   n is 0, 1, 2, 3 or 4;    -   and n+m>0;    -   each R¹ is independently selected from OH, (CH₂)₁₋₄OH,        CH_(3-a)F_(a), (CH₂)₁₋₄CH_(3-a)F_(a), OCH_(3-a)F_(a), halo,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, NO₂, CN, phenyl or a        heterocyclyl optionally substituted by C₁₋₆alkyl;    -   each R² is the group Y—X—        -   wherein each X is a linker independently selected from            —O(CH₂)₀₋₃—, —(CH₂)₀₋₃O—, —C(O)O(CH₂)₀₋₃—, —S(CH₂)₀₋₃—,            —SO(CH₂)₀₋₃—, —SO₂(CH₂)₀₋₃—, —NHSO₂, —SO₂NH—, —(CH₂)₁₋₄—,            —CH═CH(CH₂)₀₋₂—, —C≡C(CH₂)₀₋₂—, —NHCO—, —CONH—;        -   each Y is independently selected from phenyl(CH₂)₀₋₂,            naphthyl (CH₂)₀₋₂, heterocyclyl(CH₂)₀₋₂, C₃₋₇ cycloalkyl            (CH₂)₀₋₂, C₁₋₆ alkyl, OC₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆            alkynyl, or CH(OH)CH_(3-a)F_(a); where each Y is            independently optionally substituted by one or more R⁴            groups;            -   each R⁴ is independently selected from halo,                CH_(3-a)F_(a), OCH_(3-a)F_(a), CN, NO₂, NH₂, C₁₋₆alkyl,                OC₁₋₆alkyl, COOH, (CH₂)₀₋₃COOH, O(CH₂)₀₋₃COOH,                C(O)OC₁₋₆alkyl, C₁₋₆alkyl(O)OC₁₋₆alkyl, CO-phenyl,                CONH₂, CONH-phenyl, SO₂NH₂, SO₂C₁₋₆alkyl, OH, or phenyl                optionally substituted by one or more R⁵ groups where R⁵                is selected from hydrogen, C₁₋₆alkyl or C(O)OC₁₋₆alkyl.    -   each a is independently 1, 2 or 3;    -   R³ is selected from hydrogen, C₁₋₆alkyl or NHR⁶;    -   R⁶ is selected from hydrogen, C₁₋₆alkyl, OC₁₋₆alkyl,        SO₂C₁₋₆alkyl, (CH₂)₀₋₃OH;

-   with the proviso that:

-   (i) when R³ is H, m is 0, n is 2 and one of the R² groups is    phenyl-CH₂—O—, then the other R² group must be other than CH₃—S— or    CH₃—SO₂—; and

-   (ii) when R³ is H, m is 1, n is 1 and R² is phenyl-CH₂—O—, then R¹    must be other than halo.

Compounds of the invention may form salts which are within the ambit ofthe invention. Pharmaceutically acceptable salts are preferred althoughother salts may be useful in, for example, isolating or purifyingcompounds.

The term “aryl” refers to phenyl, naphthyl or a partially saturatedbicyclic carbocyclic ring containing between 8 and 12 carbon atoms,preferably between 8 and 10 carbon atoms. Example of partially saturatedbicyclic carbocyclic ring include: 1,2,3,4-tetrahydronaphthyl, indanyl,indenyl, 1,2,4a,5,8,8a-hexahydronaphthyyl or 1,3a-dihydropentalene.

The term “halo” includes fluoro, chloro, bromo and iodo; preferablychloro, bromo and fluoro; most preferably fluoro.

The expression “—CH_(3-a)F_(a)” wherein a is an integer between 1 and 3refers to a methyl group in which 1, 2 or all 3 hydrogen are replaced bya fluorine atom. Examples include: trifluoromethyl, difluoromethyl andfluoromethylene An analogous notation is used with reference to thegroup —(CH₂)₁₋₄CH_(3-a)F_(a), examples include: 2,2-difluoroethyl and3,3,3-trifluoropropyl.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups. For example, “C₁₋₄alkyl” includes propyl,isopropyl and tert-butyl.

The term “heteroaryl” refers to a monocyclic aromatic heterocyclic ringcontaining between 5–6 atoms of which at least one atom is chosen fromnitrogen, sulphur or oxygen, which may, unless otherwise specified, becarbon or nitrogen linked, wherein a —CH₂— group can optionally bereplaced by a —C(O)— and sulphur atoms in a heterocyclic ring may beoxidised to S(O) or S(O)₂ groups. Examples of “heteroaryl” include:thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-oxopyrrolidinyl,2,5-dioxopyrrolidinyl, 1,1-dioxotetrahydrothienyl,2,4-dioxoimidazolidinyl, 2-oxo-1,3,4-(4-triazolinyl),2-oxo-oxazolidininyl, 5,6-dihydrouracilyl, 1,2,4-oxadiazolyl,4-oxothiazolidinyl, morpholinyl, furanyl, 2-oxotetrahydrofuranyl,tetrahydrofuranyl, thienyl, isoxazolyl, tetrahydropyranyl, piperidyl,piperazinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl,tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, isoxazolyl,imidazolyl, pyrrolyl, thiazolyl, thiadiazolyl, isothiazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, pyranyl, pyrimidyl, pyrazinyl,pyridazinyl, pyridyl, 4-oxo-pyridinyl, 1,1-dioxotetrahydrothienyl.Preferably “heteroaryl” is selected from: pyridyl, pyrimidinyl,pyrazinyl, furanyl or thiazolyl.

The term “heterocyclyl” is a saturated, partially saturated orunsaturated, mono or bicyclic ring containing 3–12 atoms of which atleast one atom is chosen from nitrogen, sulphur or oxygen, which may,unless otherwise specified, be carbon or nitrogen linked, wherein a—CH₂— group can optionally be replaced by a —C(O)— and sulphur atoms ina heterocyclic ring may be oxidised to S(O) or S(O)₂ groups. Preferablya “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring (preferably monocyclic) containing 5 or 6 atoms ofwhich 1 to 3 atoms are nitrogen, sulphur or oxygen, which may, unlessotherwise specified, be carbon or nitrogen linked, wherein a —CH₂— groupcan optionally be replaced by a —C(O)— or sulphur atoms in aheterocyclic ring may be oxidised to S(O) or S(O)₂ groups. Examples andsuitable values of the term “heterocyclyl” are thiazolidinyl,pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl,2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl,2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl,1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl,4-thiazolidonyl, morpholino, furanyl, 2-oxotetrahydrofuranyl,tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, isoxazolyl,tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl,thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl,1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl,pyrrolyl, thiazolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl,pyridyl, 4-pyridonyl, quinolyl, tetrahydrothienyl 1,1-dioxide,2-oxo-pyrrolidinyl and 1-isoquinolonyl. Preferred examples of“heterocyclyl” when referring to a 5/6 and 6/6 bicyclic ring systeminclude benzofuranyl, benzimidazolyl, benzthiophenyl, benzthiazolyl,benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridoimidazolyl,pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl,quinazolinyl, phthalazinyl, cinnolinyl, imidazo[2,1-b][1,3]thiazolyl,chromanyl and naphthyridinyl. Preferably the term “heterocyclyl” refersto 5- or 6-membered monocyclic heterocyclic rings, such as oxazolyl,isoxazolyl, pyrrolidinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl,morpholino, furanyl, tetrahydrofuranyl, piperidyl, piperazinyl,thiomorpholino, tetrahydropyranyl, homopiperazinyl, thienyl, imidazolyl,1,24-triazolyl, 1,3,4-triazolyl, indolyl, thiazolyl, thiadiazolyl,pyrazinyl, pyridazinyl and pyridyl.

The term “cycloalkyl” refers to a saturated carbocyclic ring containingbetween 3 to 12 carbon atoms, preferably between 3 and 7 carbon atoms.Examples of C₃₋₇cycloalkyl include cycloheptyl, cyclohexyl, cyclopentyl,cyclobutyl or cyclopropyl. Preferably cyclopropyl, cyclopentyl orcyclohexyl.

Examples of C₁₋₆alkyl include methyl, ethyl, propyl, isopropyl,1-methyl-propyl, sec-butyl, tert-butyl and 2-ethyl-butyl; examples ofC₂₋₆alkenyl include: ethenyl, 2-propenyl, 2-butenyl, or2-methyl-2-butenyl; examples of C₂₋₆alkynyl include: ethynyl,2-propynyl, 2-butynyl, or 2-methyl-2-butynyl, examples of —OC₁₋₆alkylinclude methoxy, ethoky, propoxy and tert-butoxy; examples of—C(O)OC₁₋₆alkyl include methoxycarbonyl, ethoxycarbonyl andtert-butyloxycarbonyl; examples of —NH—C₁₋₄alkyl include:

and examples of —N—di-(C₁₋₄alkyl):

For the avoidance of doubt, in the definition of linker group ‘X’, theright hand side of the group is attached to phenyl ring and the lefthand side is bound to ‘Y’.

The invention includes the E and Z isomers of compounds of the inventiondefined above, but the preferred compounds are the E isomers. It is tobe understood that, insofar as certain of the compounds of the inventionmay exist in optically active or racemic forms by virtue of one or moreasymmetric carbon atoms, the invention includes in its definition anysuch optically active or racemic form which possesses the property ofstimulating GLK directly or inhibiting the GLK/GLKRP interaction. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form.

Preferred compounds of Formula (I) to (Ic) above or of Formula (II) to(IIf) below are those wherein any one or more of the following apply:

-   (1) m is 0 or 1;    -   n is 1 or 2; preferably n is 2;    -   most preferably m is 0 and n is 2.-   (2) The R¹ and/or R² group(s) are attached at the 2-position and/or    the 3-position and/or the 5-position; when n+m is 2, the groups are    preferably at the 2- and 5- or 3- and 5- positions, most preferably    at the 2- and 5- positions.-   (3) each R¹ is independently selected from OH, CH_(3-a)F_(a)    (preferably CF₃), OCH_(3-a)F_(a) (preferably OCF₃), halo, C₁₋₆alkyl    (preferably methyl), NO₂ or heterocyclyl optionally substituted by    C1-6alkyl, preferably R₁ is selected from CH_(3-a) F_(a) (preferably    CF₃), OCH_(3-a)F_(a) (preferably OCF₃ ) or halo;-   (4) each R² is the group Y—X—    -   wherein each X is independently selected from:        -   —O—Z—, —C(O)O—Z—, —S—Z—, —SO—Z—, —SO₂—Z—, —N(R⁶)SO₂,Z—            —SO₂NH—Z—, —(CH₂)₁₋₄—, —CH═CH—Z—, —C≡C—C—Z—, —N(R⁶)CO—Z—,            —CON(R⁶)—Z— or a direct bond;        -   Preferably X is independently selected from: —O—Z—, —S—Z—,            —SO—Z—, —SO₂—Z, —N(R⁶)SO₂, Z— —SO₂NH—Z— —(CH₂)₁₋₄— or a            direct bond        -   Most preferably X is independently selected from: —O—, —S—,            —SO—, —SO₂—, —(CH₂)₁₋₄— or a direct bond;    -   each Z is independently selected from:        -   a direct bond or —(CH₂)₁₋₂, or a group of the formula            —(CH₂)_(p)—C(R⁶)₂—(CH₂)_(q)—, wherein one R⁶ group is            hydrogen and the other R⁶ group is C₁₋₄alkyl;        -   preferably a direct bond, —(CH₂)₀₋₂— or

-   -   -   more preferably a direct bond or —CH₂—.

    -   each Z¹ is independently selected from:        -   a direct bond, C₂₋₆alkenylene or a group of the formula        -   —(CH₂)_(p)—C(R⁶)₂—(CH₂)_(q)—, wherein one R⁶ group is            hydrogen and the other R⁶ group is C₁₋₄alkyl;        -   preferably a direct bond, —(CH₂)₀—, C₂₋₄alkenylene or

-   -   -   more preferably a direct bond, —(CH₂)₀₋₄—, 2-propenylene or

-   -   -   most preferably —(CH₂)₀₋₃—, 2-propenylene or a direct bond.

    -   and each Y is independently selected from:        -   aryl-Z¹—, heterocyclyl-Z¹—, C₃₋₇cycloalkyl-Z¹—, C₁₋₆ alkyl,            C₁₋₆alkoxy, C₂₋₆alkenyl or —CH(OH)CH_(3-a)F_(a);        -   preferably each Y is independently selected from:            -   phenyl-Z¹—, heterocyclyl-Z¹—, C₃₋₇cycloalkyl-Z¹—, C₁₋₆                alkyl (preferably a branched C₂₋₆alkyl chain such as                isopropyl or isobutyl), C₂₋₆alkenyl or —CH_(3-a)F_(a);        -   most preferably Y is independently selected from:            -   phenyl-Z¹—, morpholinyl-Z¹—, pyridyl-Z¹—,                pyrrolidino-Z¹—, isoxazolyl-Z¹—, diazolyl-Z¹—,                furanyl-Z¹—, thienyl-Z¹—, thiazolyl-Z¹—, cyclopropyl-Z¹—                or cyclohexyl-Z¹—,

    -   wherein each Y is independently optionally substituted by R⁴.

-   (5) each R² is the group Y—X, Z within the definition of X is a    direct bond and Z¹ within the definition of Y is a group of the    formula —(CH₂)_(p)—C(R⁶)₂—(CH₂)_(q)—.    -   most preferably R² is independently selected from: methoxy,        methylthio, methylsulphinyl, methylsulphonyl, ethoxy,        iso-propoxy, pentyloxy, phenoxy, benzyloxy, phenylpropoxy,        phenylallyloxy, phenylthio, diazolylmethoxy, diazolylethoxy,        furanylmethoxy, isoxazolylmethoxy, morpholino, pyridylmethoxy,        pyrrolidinylethoxy, thiazolyl, thiazolylmethoxy, thiazolyethoxy,        thienylmethoxy, cyclopropylmethoxy, or cyclohexylmethoxy,        wherein each of these R² groups is optionally substituted by R⁴.

-   (6) each R⁴ is independently selected from:    -   halo, —CH₃₋₆F_(a), —OCH_(3-a)F_(a), CN, NO₂, C₁₋₆alkyl,        C₁₋₆alkoxy, —COOH, —(CH₂)₁₋₃COOH, —(CH₂)₀₋₃COOH, —C(O)phenyl,        —C(O)NH₂, —C(O)NH-phenyl, —SO₂NH₂, —SO₂C₁₋₆alkyl, phenyl        optionally substituted by C₁₋₆alkyl or —C(O)OC₁₋₆alkyl;    -   More preferably R⁴ is independently selected from, chloro,        bromo, fluoro, methyl, tert-butyl, isopropyl, methoxy,        C₁₋₄alkoxycarbonyl, vinyl, CN, OH, trifluoromethyl, —COOH,        —CH₂COOH, NO₂, methylsulphonyl, —C(O)NH₂, —C(O)NH-phenyl,        —SO₂NH₂ or benzyloxy.

-   (7) R³ is selected from hydrogen or C₁₋₆alkyl; preferably R³ is    selected from hydrogen or methyl; most preferably R³ is hydrogen.

According to a further feature of the invention there is provided thefollowing preferred groups of compounds of the invention.

-   (I) a compound of Formula (II)

wherein:A, X, Z¹, R³ and R⁴ are as defined above in a compound of Formula (I);or a salt, solvate or pro-drug thereof.

-   (II) a compound of Formula (IIa)

wherein:Het is a monocyclic heterocyclyl, optionally substituted with between 1and 3 groups selected from R⁴ and,A, X, Z¹, R³ and R⁴ are as defined above in a compound of Formula (I):or a salt, solvate or pro-drug thereof.

-   (III) a compound of Formula (IIb)

wherein

-   -   the C₁₋₆alkyl group is optionally substituted with between 1 and        3 groups selected from R⁴, preferably unsubstituted;    -   the C₁₋₆alkyl group optionally contains a double bond,        preferably the C₁₋₆alkyl group does not contains a double bond;        and    -   A, X, Z¹, R³ and R⁴ are as defined above in a compound of        Formula (I); with the proviso that:    -   when A is pyridyl, R³ is OH, phenyl-Z¹—X— is phenyl-CH₂—O—        wherein the phenyl ring is unsubstituted, then C₁₋₆alkyl-X— must        be other than CH₃—S— or CH₃—SO₂—; or a salt, solvate, or        pro-drug thereof.

-   (IV) a compound of Formula (IIc)

wherein:

-   -   the C₃₋₇cycloalkyl group is optionally substituted with between        1 and 3 groups selected from R⁴, and    -   A, X, Z¹, R³ and R⁴ are as defined above in a compound of        Formula (I); or a salt, solvate or pro-drug thereof.

-   (V) a compound of Formula (IId)

wherein:

-   -   the C₁₋₆alkyl groups are independently optionally substituted        with between 1 and 3 groups selected from R⁴, preferably one of        the C₁₋₆alkyl groups is unsubstituted, the C₁₋₆alkyl groups        independently optionally contain a double bond, preferably only        one of the C₁₋₆alkyl groups contain a double bond, preferably        neither of the C₁₋₆alkyl group contains a double bond, and    -   A, X, R³ and R⁴ are as defined above in a compound of Formula        (I); with the proviso that A is other than pyridyl, furanyl or        thiazolyl; or a salt, solvate or pro-drug thereof.

-   (VI) a compound of Formula (IIe)

wherein

-   -   the C₁₋₆alkyl groups are independently optionally substituted        with between 1 and 3 groups selected from R⁴, preferably one of        the C₁₋₆alkyl groups is unsubstituted, the C₁₋₆alkyl groups        independently optionally contain a double bond, preferably only        one of the C₁₋₆alkyl groups contain a double bond, preferably        neither of the C₁₋₆alkyl group contains a double bond, and    -   A, X, R³ and R⁴ are as defined above in a compound of Formula        (I); with the proviso that A is other than pyridyl, furanyl or        thiazolyl; or a salt, solvate or pro-drug thereof.

-   (VII) a compound of Formula (IIf)

wherein

-   -   Het is a monocyclic heterocyclyl,    -   the Het and C₁₋₆alkyl groups are independently optionally        substituted with between 1 and 3 groups selected from R⁴,        preferably the C₁₋₆alkyl group is unsubstituted;    -   the C₁₋₆alkyl group optionally contains a double bond,        preferably the C₁₋₆alkyl group does not contains a double bond;        and    -   A, X, Z¹, R³ and R⁴ are as defined above in a compound of        Formula (I); or a salt, solvate or pro-drug thereof.

-   (VIII) a compound of Formula (IIg)

wherein:

-   -   Het is a monocyclic heterocyclyl,    -   the Het and C₃₋₇cycloalkyl groups are independently optionally        substituted with between 1 and 3 groups selected from R⁴, and    -   A, X, Z¹, R³ and R⁴ are as defined above in a compound of        Formula (I); or a salt, solvate or pro-drug thereof.

-   (IX) a compound of Formula (IIh)

wherein:

-   -   Y is aryl-Z¹—, wherein aryl is preferably a partially saturated        bicyclic carbocyclic ring;    -   Y and the C₁₋₆alkyl group are independently optionally        substituted with between 1 and 3 groups selected from R⁴,        preferably the C₁₋₆alkyl group is unsubstituted,    -   the C₁₋₆alkyl group optionally contains a double bond,        preferably the C₁₋₆alkyl group does not contains a double bond;        and    -   A, X, Z¹, R³ and R⁴ are as defined above in a compound of        Formula (I); or a salt, solvate or pro-drug thereof.

-   (X) a compound of Formula (IIj)

wherein:

-   -   X is selected from —SO₂N(R⁶)—Z— or —N(R⁶)SO₂—Z—, preferably X is        —SO₂N(R⁶)—Z—;    -   Z is as described above, preferably Z is propylene, ethylene or        methylene, more preferably Z is methylene;    -   Z^(a) is selected from a direct bond or a group of the formula        —(CH₂)_(p)—C(R⁶ ₂—(CH₂)_(q)—; preferably Z^(a) is selected from        C₁₋₂alkylene or a direct bond; preferably Z^(a) is a direct        bond;    -   R⁶ is selected from: C₁₋₄alkyl or hydrogen, preferably methyl or        hydrogen;    -   Y is selected from aryl-Z¹— or heterocyclyl-Z¹—;    -   Y and the C₁₋₆alkyl group are independently optionally        substituted with between 1 and 3 groups selected from R⁴,    -   the C₁₋₆alkyl group optionally contains a double bond,        preferably the C₁₋₆alkyl group does not contain a double bond,        and    -   A, Z¹, R³ and R⁴ are as defined above in a compound of Formula        (I); or a salt, solvate or pro-drug thereof.

A further preferred groups of compounds of the invention in either ofgroups (I)–(IX) above is wherein:

-   -   X is independently selected from —O—Z—, SO₂N(R⁶)—Z— or        —N(R⁶)—Z—;    -   Z is a direct bond or —CH₂—;    -   Z¹ is selected from a direct bond, —CH₂— —(CH₂)₂— or

-   -   R³ is as defined above in a compound of Formula (I); or a salt,        solvate or pro-drug thereof.

In a further embodiment of the invention there is provided a compound asdefined in either of groups (I) to (X) above wherein:

A is selected from: pyridyl, pyrimidinyl, pyrazinyl, furanyl orthiazolyl; preferably A is linked to the styryl group at the 2-positionof A.

In a further embodiment of the invention there is provided a compound asdefined in either of groups (I) to (X) above wherein the two Y—X— groupsare linked to the phenyl ring in a 2,5 orientation relative to thestyryl group.

The compounds of the invention may be administered in the form of apro-drug. A pro-drug is a bioprecursor or pharmaceutically acceptablecompound being degradable in the body to produce a compound of theinvention (such as an ester or amide of a compound of the invention,particular an in vivo hydrolysable ester). Various forms of prodrugs areknown in the art. For examples of such prodrug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309–396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen;-   c) H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”,    by H. Bundgaard p. 113–191 (1991);-   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1–38 (1992);-   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988); and-   f) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).-   The contents of the above cited documents are incorporated herein by    reference.

Examples of pro-drugs are as follows. An in-vivo incorporated herein byreference compound of the invention containing a carboxy or a hydroxygroup is, for example, a pharmaceutically-acceptable ester which ishydrolysed in the human or animal body to produce the parent acid oralcohol. Suitable pharmaceutically-acceptable esters for carboxy includeC₁ to C₆alkoxymethyl esters for example methoxymethyl, C₁ to₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, C₃ to ₈cycloalkoxycarbonyloxyC₁ to ₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters.

An in-vivo hydrolysable ester of a compound of the invention containinga hydroxy group includes inorganic esters such as phosphate esters(including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers andrelated compounds which as a result of the in-vivo hydrolysis of theester breakdown to give the parent hydroxy group/s. Examples ofα-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysable esterforming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a benzoxazinone derivative of theinvention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, and ammonium salt or a salt with anorganic base which affords a physiologically-acceptable cation, forexample a salt with methylamine; dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

A further feature of the invention is a pharmaceutical compositioncomprising a compound of Formula (I) to (Ic) or (II) to (IIj) as definedabove, or a salt, solvate or prodrug thereof, together with apharmaceutically-acceptable diluent or carrier.

According to another aspect of the invention there is provided acompound of Formula (Ib) or (Ic), or (II) to (IIj) as defined above foruse as a medicament; with the proviso that

-   (i) when A is pyridyl or thiazolyl, m is 1 or 2 and n is 0, R³ is OH    or —O-C₁₋₆alkyl, then R¹ is other than halo, amino or nitro;-   (ii) when A is pyridyl m=0, n=1, X is —N(CH₃)— or —N(CH₃)—CH₂—, R³    is OH, then Y cannot be methyl;-   (iii) when A is thiazolyl. m is 0, R³ is OH, then when n is 2    (R²)_(n) cannot be di-C₁₋₆alkyl-O— or C₁₋₆alkyl-O-C₁₋₆alkenyl-O— and    when n is 3 (R²)_(n) cannot be tri-C₁₋₆alkyl-O—;-   (iv) when A is pyridyl, m is 0 or m is 1 and R¹ and R¹ is halo, n is    1 and R² is phenyl-CH₂—O—, then R³ cannot be OH; and-   (v) when A is pyridyl, R³ is OH, m is 0, n is 2 and one of the R²    groups is phenyl-CH₂—O—, then the other R² group must be other than    CH₃—S— or CH₃—SO₂—.

Further according to the invention there is provided a compound ofFormula (Ib) or (Ic), or (II) or (IIj) for use in the preparation of amedicament for treatment of a disease mediated through GLK, inparticular type 2 diabetes.

The compound is suitably formulated as a pharmaceutical composition foruse in this way.

According to another aspect of the present invention there is provided amethod of treating GLK mediated diseases, especially diabetes, byadministering an effective amount of a compound of Formula (Ib) or (Ic),or (II) to (IIj) to a mammal in need of such treatment.

Specific disease which may be treated by the compound or composition ofthe invention include: blood glucose lowering in Diabetes Mellitus type2 without a serious risk of hypoglycaemia (and potential to treat type1), dyslipidemea, obesity, insulin resistance, metabolic syndrome X,impaired glucose tolerance.

Specific disease which may be treated by the compound or composition ofthe invention include: blood glucose lowering in Diabetes Mellitus type2 (and potential to treat type 1); dyslipidaemia; obesity; insulinresistance; metabolic syndrome X; impaired glucose tolerance; polycysticovary syndrome.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing.)

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl-p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or n a mineral agent such as beeswax, hard paraffin orcetyl alcohol. Sweetening agents such as those set out above, andflavouring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an anti-oxidantsuch as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxides such aspolyoxyethylene sorbitan monooleate. The emulsions may also containingsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The size of the does for therapeutic or prophylactic purposes of acompound of the Formula (I), (Ia), (Ib) or (Ic) will naturally varyaccording to the nature and severity of the conditions, the age and sexof the animal or patient and the route of administration, according towell known principles of medicine.

In using a compound of the Formula (I), (Ia), (Ib) or (Ic) fortherapeutic or prophylactic purposes it will generally be administeredso that a daily dose in the range, for example, 0.5 mg to 75 mg per kgbody weight is received, given if required in divided doses. In generallower doses will be administered when a parenteral route is employed.Thus, for example, for intravenous administration, a dose in the range,for example, 0.5 mg to 30 mg per kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.5 mg to 25 mg per kg body weight will be used. Oraladministration is however preferred.

The elevation of GLK activity described herein may be applied as a soletherapy or may involve, in addition to the subject of the presentinvention, one or more other substances and/or treatments. Such conjointtreatment may be achieved by way of the simultaneous, sequential orseparate administration of the individual components of the treatment.Simultaneous treatment may be in a single tablet or in separate tablets.For example in the treatment of diabetes mellitus chemotherapy mayinclude the following main categories of treatment:

-   1) Insulin and insulin analogues;-   2) Insulin secretagogues including sulphonylureas (for example    gibenclamide, glipizide) and prandial glucose regulators (for    example repaglinide, nateglinide);-   3) Insulin sensitising agents including PPARg agonists (for example    pioglitazone and rosiglitazone);-   4) Agents that suppress hepatic glucose output (for example    metformin).-   5) Agents designed to reduce the absorption of glucose from the    intestine (for example acarbose);-   6) Agents designed to treat the complications of prolonged    hyperglycaemia;-   7) Anti-obesity agents (for example sibutramine and orlistat);-   8) Anti-dyslipidaemia agents such as, HMG-CoA reductase inhibitors    (statins, eg pravastatin); PPARα agonists (fibrates, eg    gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol    absorption inhibitors (plant stanols, synthetic inhibitors); bile    acid absorption inhibitors (IBATi) and nicotinic acid and analogues    (niacin and slow release formulations);-   9) Antihypertensive agents such as, β blockers (eg atenolol,    inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg.    nifedipine); Angiotensin receptor antagonists (eg candesartan), α    antagonists and diuretic agents (eg. furosemide, benzthiazide);-   10) Haemostasis modulators such as, antithrombotics, activators of    fibrinolysis and antiplatelet agents; thrombin antagonists; factor    Xa inhibitors; factor VIIa inhibitors); antiplatelet agents (eg.    aspirin, clopidogrel); anticoagulants (heparin and Low molecular    weight analogues, hirudin) and warfarin; and-   11) Anti-inflammatory agents, such as non-steroidal    anti-inflammatory drugs (eg. aspirin) and steroidal    anti-inflammatory agents (eg. cortisone).

According to another aspect of the present invention there is providedindividual compounds produced as end products in the Examples set outbelow and salts thereof.

A compound of the invention, or a salt, pro-drug or solvate thereof, maybe prepared by any process known to be applicable to the preparation ofsuch compounds or structurally related compounds. Such processes areillustrated by the following representative schemes (1 to 4) in whichvariable groups have nay of the meanings defined for Formula (I) unlessstated otherwise and A is for example depicted as pyridyl. Functionalgroups may be protected and deprotected using conventional methods.

For examples of protecting groups such as amino and carboxylic acidprotecting groups (as well as means of formation and eventualdeprotection), see T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, Second Edition, John Wiley & Sons, New York, 1991.Note abbreviations used have been listed immediately before the Examplesbelow.

During the preparation process, it may be advantageous to use aprotecting group for a functional group within the molecule. Protectinggroups may be removed by any convenient method as described in theliterature or known to the skilled chemist and appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Processes for the synthesis of compounds of Formula (I) are provided asa further feature of the invention. Thus, according to a further aspectof the invention there is provided a process for the preparation of acompound of Formula (I) which comprises:

-   (a) reaction of a compound of Formula (IIa) with a compound of    Formula (IIIb),

-   (b) for compounds of Formula (I) wherein R³ is hydrogen,    de-protection of a compound of Formula (IIIc),

wherein P¹ is a protecting group;

-   (c) reaction of a compound of Formula (IIId) with a compound of    Formula (IIIe),

wherein X′ and X″ comprises groups which when reacted together form thegroup X;

-   (d) for a compound of Formula (I) wherein X or X¹ is —SO—Z—,    —SO₂—Z—, oxidation of the corresponding compound of Formula (I)    wherein X or X¹ respectively is —S—Z—; or-   (e) for a compound of Formula (I) wherein R³ is NHR⁶, reaction of a    compound of Formula (IIIf) with a compound of Formula (IIIg),

and thereafter, if necessary:

-   i) converting a compound of Formula (I) into another compound of    Formula (I);-   ii) removing any protecting groups;-   iii) forming a salt, pro-drug or solvate thereof.

Specific reaction conditions for the above reactions are as follows:

-   Process a)—as described above in Scheme 1;-   Process b)—as described above in Scheme 1/2-   Process c)—examples of this process are as follows:    -   (i) to form a group when X is —O—Z—, X′ is a group of formula        HO—Z— and X″ is a leaving group (alternatively X′ is a group of        formula L²—Z— wherein L² is a leaving group and X″ is a hydroxyl        group), compounds of Formula (IIId) and (IIIe) are reacted        together in a suitable solvent, such as DMF or THF, with a base        such as sodium hydride or potassium tert-butoxide, at a        temperature in the range 0 to 100° C., optionally using metal        catalysis such as palladium on carbon or cuprous iodide;    -   (ii) to form a group when X is N(R⁶)—Z—, X′ is a group of        formula H—(R⁶)N—Z— and X″ is a leaving group (alternatively X′        is a group of formula L²—X— wherein L² is a leaving group and X″        is a group or formula —N(R⁶)—H), compounds of Formula (IIId) and        (IIIe) are reacted together in a suitable solvent such as THF,        an alcohol or acetonitrile, using a reducing agent such as        sodium cyano borohydride or sodium trisacetoxyborohydride at        room temperature;    -   (iii) to form a group when X is —SO₂N(R⁶)—Z—, X′ is a group of        formula H—N(R⁶)—Z— wherein L² is a leaving group and X″ is an        activated sulphonyl group such as a group of formula —SO₂—Cl,        compounds of Formula (IIId) and (IIIe) are reacted together in a        suitable solvent such as methylene chloride, THF or pyridine, in        the presence of a base such as triethylamine or pyridine at room        temperature;    -   (iv) to form a group when X is —N(R⁶)SO₂—Z—, X′ is an activated        sulphonyl group such as a group of formula Cl—SO₁—Z— group and        X″ is a group of formula —N(R⁶)—L² wherein L² is a leaving        group, compounds of Formula (IIId) and (IIIe) are reacted        together in a suitable solvent such as methylene chloride, THF        or pyridine, in the presence of a base such as triethylamine or        pyridine at room temperature;    -   (v) to form a group when X is —C(O)N(R⁶)—Z—, X′ is a group of        formula H—N(R⁶)—Z— wherein L² is a leaving group and X″ is an        activated carbonyl group such as a group of formula —C(O)—Cl,        compounds of Formula (IIId) and (IIIe) are reacted together in a        suitable solvent such as THF or methylene chloride, in the        presence of a base such as triethylamine or pyridine at room        temperature;    -   (vi) to form a group when X is —N(R⁶)C(O)—Z—, X′ is an activated        carbonyl group such as a group of formula Cl—C(O)—Z— group and        X″ is a group of formula —N(R⁶)—L² wherein L² is a leaving        group, compounds of Formula (IIId) and (IIIe) are reacted        together in a suitable solvent such as THF or methylene        chloride, in the presence of a base such as triethylamine or        pyridine at room temperature;    -   (vii) to form a grouped when X is —CH═CH—Z—, a Wittag reaction        or a Wadsworth-Emmans Horner reaction can be used. For example,        X′ terminates in an aldehyde group and Y—X″ is a phosphine        derivative of the formula Y—C⁻H—P⁺PH₃ which can be reacted        together in a strong base such as sodium hydride or potassium        tert-butoxide, in a suitable solvent such as THF at a        temperature between room temperature and 100° C.-   Process d)—the oxidization of a compound of Formula (I) wherein X or    X¹ is —S—Z— is well known in the art, for example, reaction with    metachloroperbenzoic acid (MCPBA) is the presence of a suitable    solvent such as dichloromethane at ambient temperature. If an excess    of MCPBA is used a compound of Formula (I) wherein X is —S(O₂)— is    obtained.-   Process e)—as described above in Scheme 4.

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower” signifies that the group to which it isapplied preferably has 1–4 carbon atoms. It will be understood thatthese examples are not exhaustive. Where specific examples of methodsfor the removal of protecting groups are given below these are similarlynot exhaustive. The use of protecting groups and methods of deprotectionnot specifically mentioned is of course within the scope of theinvention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or araliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1–20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(C₁₋₁₂)alkyl groups (e.g. isopropyl, t-butyl); lower alkoky lower alkylgroups (e.g. methoxymethyl, ethoxymethyl, isobutoxymethyl; loweraliphatic acyloxy lower alkyl groups, (e.g. acetoxymethyl,propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); loweralkoxycarbonyloxy lower alkyl groups (e.g. 1-methoxycarbonyloxyethyl,1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (e.g.p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl andphthalidyl); tri(lower alkyl)silyl groups (e.g. trimethylsilyl andt-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (e.g.trimethylsilylethyl); and (2-6C)alkenyl groups (e.g. allyl andvinylethyl).

Methods particularly appropriate for the removal of carboxyl protectinggroups include for example acid-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxy protecting groups include lower alkenyl groups (e.g.allyl); lower alkanoyl groups (e.g. acetyl); lower alkoxycarbonyl groups(e.g. t-butoxycarbonyl); lower alkenyloxycarbonyl groups (e.g.allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g.benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkyl/arylsilyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl); aryl lower alkyl groups (e.g. benzyl) groups; andtriaryl lower alkyl groups (e.g. triphenylmethyl).

Examples of amino protecting groups include formyl, aralkyl groups (e.g.benzyl and substituted benzyl, e.g., p-methoxybenzyl, nitrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl andfurylmethyl groups; lower alkoxycarbonyl (e.g. t-butoxycarbonyl); loweralkenyloxycarbonyl (e.g. allyloxycarbonyl); aryl lower alkoxycarbonylgroups (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (e.g.trimethylsilyl and t-butyldimethylsilyl); alkylidene (e.g. methylidene);benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base, metal- or enzymically-catalysedhydrolysis, or photolytically for groups such aso-nitrobenzyloxycarbonyl, or with fluoride ions for silyl groups.

Examples of protecting groups for amide groups include aralkoxymethyl(e.g. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl(e.g. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl(e.g. trimethylsilyl, t-butyldimethylsily, t-butyldiphenylsilyl); trialkyl/arylsilyloxymethyl (e.g. t-butyldimethylsilyloxymethyl,

t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (e.g. 4-methoxyphenyl);2,4-di(alkoxy)phenyl (e.g. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (e.g.4-methoxybenzyl); 2,4-di(alkoxy)benzyl (e.g. 2,4di(methoxy)benzyl); andalk-1-enyl (e.g. allyl, but-1-enyl and substituted vinyl e.g.2-phenylvinyl).

Aralkoxymethyl, groups may be introduced onto the amide group byreacting the latter group with the appropriate aralkoxymethyl chloride,and removed by catalytic hydrogenation. Alkoxymethyl, trialkyl/arylsilyl and tri alkyl/silyloxymethyl groups may be introduced byreacting the amide with the appropriate chloride and removing with acid;or in the case of the silyl containing groups, fluoride ions. Thealkoxyphenyl and alkoxybenzyl groups are conveniently introduced byarylation or alkylation with an appropriate halide and removed byoxidation with ceric ammonium nitrate. Finally alk-1-enyl groups may beintroduced by reacting the amide with the appropriate aldehyde andremoved with acid.

The present invention also relates to the use of a GLK activator for thecombined treatment of diabetes and obesity. GLK and GLKRP and theK_(ATP) channel are expressed in neurones of the hypothalamus, a regionof the brain that is important in the regulation of energy balance andthe control of food intake [14–18 . These neurones have been shown toexpress orectic and anorectic neuropeptides [15, 19, 20] and have beenassumed to be the glucose-sensing neurones within the hypothalamus thatare either inhibited or excited by changes in ambient glucoseconcentrations [17, 19, 21, 22]. The ability of these neurones to sensechanges in glucose levels is defective in a variety of genetic andexperimentally induced models of obesity [23–28].Intracerebroventricular (icv) infusion of glucose analogues, that arecompetitive inhibitors of glucokinase, stimulate food intake in leanrats [29, 30]. In contrast, icv infusion of glucose suppresses feeding[31]. Thus, small molecule activators of GLK may decrease food intakeand weight gain through central effects on GLK. Therefore, GLKactivators may be of therapeutic use in treating eating disorders,including obesity, in addition to diabetes. The hypothalamic effectswill be additive or synergistic to the effects of the same compoundsacting in the liver and/or pancreas in normalising glucose homeostasis,for the treatment of Type 2 diabetes. Thus the GLK/GLKRP system can bedescribed as a potential “Diabesity” target (of benefit in both Diabetesand Obesity).

This according to a second aspect of the invention there is provided theuse of a GLK activator in the preparation of a medicament for thecombined treatment or prevention of diabetes and obesity.

According to a further feature of the second aspect of the inventionthere is provided a method of combined treatment, in a warm-bloodedanimal, of diabetes and obesity, comprising administering atherapeutically effective amount of a compound of a GLK activator, or apharmaceutically-acceptable salt, pro-drug or solvate thereof.

According to a further feature of the second aspect of the inventionthere is provided a pharmaceutical composition comprising a GLKactivator, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in admixture with a pharmaceutically-acceptable diluent orcarrier for the combined treatment of diabetes and obesity in awarm-blooded animal.

According to a further feature of the second aspect of the inventionthere is provided to use a GLK activator in the preparation of amedicament for the treatment or prevention of diabetes and obesity,wherein the GLK activator is a compound of Formula (I) above.

According to a further feature of the second aspect of the inventionthere is provided a method of combined treatment, in a warm-bloodedanimal, of diabetes and obesity, comprising administering atherapeutically effective amount of a compound of a GLK activator, or apharmaceutically-acceptable salt, pro-drug or solvate thereof, whereinthe GLK activator is a compound of Formula (I) above.

According to a further features of the second aspect of the inventionthere is provided a pharmaceutical composition comprising a GLKactivator, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in admixture with a pharmaceutically-acceptable diluent orcarrier for the combined treatment of diabetes and obesity in awarm-blooded animal, wherein the GLK activator is a compound of Formula(I) above.

According to a further feature of the second aspect of the inventionthere is provided the use of a GLK activator in the preparation of amedicament for the treatment or prevention of diabetes and obesity,wherein the GLK activator is a compound of Formula (IV) below.

wherein

-   m is 0, 1 or 2;-   n is 0, 1, 2, 3 or 4;-   and n+m>0;-   each R¹ is independently selected from OH, —(CH₂)₁₋₄OH,    —CH_(3-a)F_(a), —(CH₂)₁₋₄CH_(3-a)F_(a), halo, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, NO₂, NH₂, —NH—C₁₋₄alkyl,    —N-di-(C₁₋₄alkyl), CN or formula;-   each R² is the group Y—X—    -   wherein each X is a linker independently selected from:        -   —O—Z—, —O—Z—O—Z, —C(O)O—Z—, —OC(O)—Z—, —S—Z—, —SO—Z—,            —SO₂—Z—, —N(R⁶)—Z—, —N(R⁶)SO₂—Z, —SO₂N(R⁶)—Z—, —(CH₂)₁₋₄—,            —CH═CH—Z—, —C≡C—Z—, —N(R⁶)CO—Z—, —CON(R⁶)—Z—,            —C(O)N(R⁶)S(O)₂—Z—, —S(O)₂N(R⁶)C(O)—Z—, —C(O)—Z— or a direct            bond;    -   each Z is independently a direct bond or a group of the formula        —CH₂)_(p)—C(R⁶)₂—(CH₂)_(q)—;    -   each Y is independently selected from aryl-Z¹—,        heterocyclyl-Z¹—, C₃₋₇cycloalkyl-Z¹—, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl or —(CH₂)₁₋₄CH_(3-a)F_(a);        -   wherein each Y is independently optionally substituted by up            to 3 R⁴ groups;        -   each R⁴ is independently selected from halo, —CH_(3-a)F_(a),            CN, NO₂, NH₂, C₁₋₆alkyl, —OC₁₋₆alkyl, —COOH,            —C(O)OC₁₋₆alkyl, OH or phenyl,            -   or R⁵—X¹—, where X¹ is independently as defined in X                above and R⁵ is selected from hydrogen, C₁₋₆alkyl,                —CH_(3-a)F_(a), phenyl, naphthyl, heterocyclyl or                C₃₋₇cycloalkyl; and R⁵ is optionally substituted by                halo, C₁₋₆alkyl, —CH_(3-a)F_(a), CN, NO₂, NH₂, COOH or                —C(O)OC₁₋₆alkyl,            -   wherein each phenyl, naphthyl or heterocyclyl ring in R⁵                is optionally substituted by halo, CH_(3-a)F_(a), CN,                NO₂, NH₂, C₁₋₆alkyl, —OC₁₋₆alkyl, COOH, —C(O)OC₁₋₆alkyl                or OH;        -   each Z¹ is independently a direct bond or a group of the            formula —(CH₂)_(p)—C(R⁶)₂—(CH₂)_(q);    -   R³ is selected from hydrogen or C₁₋₆alkyl; and    -   R⁶ is independently selected from hydrogen, C₁₋₆alkyl or        —C₂₋₄alkyl-O-C₁₋₄alkyl;    -   each a is independently 1,2 or 3;    -   p is an integer between 0 and 2;    -   q is an integer between 0 and 2;    -   and p+q<4.

According to a further feature of the second aspect of the inventionthere is provided a method of combined treatment, in a warm-bloodedanimal, of diabetes and obesity, comprising administering atherapeutically effective amount of a compound of a GLK activator, or apharmaceutically-acceptable salt, pro-drug or solvate thereof, whereinthe GLK activator is a compound of Formula (IV).

According to a further feature of the second aspect of the inventionthere is provided a pharmaceutical composition comprising a GLKactivator, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in admixture with a pharmaceutically-acceptable diluent orcarrier for the combined treatment of diabetes and obesity in awarm-blooded animal, wherein the GLK activator is a compound of Formula(IV).

Further examples of GLK activators are contained in InternationalApplication numbers: WO 00/58293, WO 01/44216, WO 01/83465, WO 01/83478,WO 01/85706, WO 01/85707, WO 02/08209 and WO 02/14312. The contents ofaforesaid International Applications are hereby incorporated byreference.

In a further feature of the second aspect of the invention there isprovided the use of a GLK activator in the preparation of a medicamentfor the treatment or prevention of diabetics and obesity, wherein theGLK activator is a compound exemplified in aforesaid InternationalApplications or falls within the scope of aforesaid InternationalApplications.

According to a further feature of the second aspect of the inventionthere is provided a method of combined treatment, in a warm-bloodedanimal, of diabetes and obesity, comprising administering atherapeutically effective amount of a compound of a GLK activator,wherein the GLK activator is a compound exemplified in aforesaidInternational Applications or falls within the scope of aforesaidInternational Applications.

According to a further feature of the second aspect of the inventionthere is provided a pharmaceutical composition comprising a GLKactivator, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in admixture with a pharmaceutically-acceptable diluent orcarrier for the combined treatment of diabetes and obesity in awarm-blooded animal, wherein the GLK activator is a compound exemplifiedin aforesaid International Applications or falls within the scope ofaforesaid International Applications.

The identification of compounds that are useful in the combinedtreatment of diabetes and obesity is the subject of the presentinvention. These properties may be assessed, for example, by measuringchanges in food intake, feeding-related behaviour (eg. feeding,grooming, physical activity, rest) and body weight separately ortogether with measuring plasma or blood glucose or insulinconcentrations with or without an oral glucose load/food in a variety ofanimal models such as ob/ob mouse, db/db mouse, Fatty Zucker rat, Zuckerdiabetic rate (ZDF), a streptozotocin-treated rats or mice ordiet-induced obese mice or rats, as described in Sima & Shafrir, 2001,Animal Models of Diabetes. A Primer (Harwood Academic Publishers,Netherlands) or in animals treated with glucose directly into the brainor in animals rendered diabetic by treatment with streptozotocin and feda high fat diet (Metabolism 49: 1390–4, 2000).

GLK activators may be used in the combined treatment of diabetes andobesity alone or in combination with one or more additional therapies.Such combination therapy may be achieved by way of the simultaneous,sequential or separate administration of the individual components ofthe treatment. Simultaneous treatment may be in a single table or inseparate tablets. Examples of agents which may be used in combinationtherapy include those listed in paragraphs 1)–11) above, as drugs whichmay be used with compounds of Formula (I).

The following examples of Compounds of Formula (I)–(Ic) are forillustration purposes and are not intended to limit the scope of thisapplication. Each exemplified compound represents a particular andindependent aspect of the invention. In the following non-limitingExamples, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at room temperature, that is in therange 18–25° C. and under an atmosphere of an inert gas such as argon ornitrogen;

(iii) yields are given for illustration only and are not necessarily themaximum attainable;

(iv) the structures of the end-products of the Formula (I) wereconfirmed by nuclear (generally proton) magnetic resonance (NMR) andmass spectral techniques; proton magnetic resonance chemical shiftvalues were measured on the delta scale and peak multiplicities areshown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,broad; q, quartet, quin, quintet;

(v) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;

(vi) chromatography was performed on silica (Merck Silica gel 60,0.040–0.063 mm, 230–400 mesh); and

(vi) Biotage cartridges refer to pre-packed silica cartridges (from 40 gup to 400 g), eluted using a biotage pump and fraction collector system;Biotage UK Ltd, Hertford, Herts, UK.

EXAMPLE A Scheme 1: Preparation of6-(E-3-phenoxy-phenyl]-vinyl)-nicotinic Acid

To a mixture of 6- methylnicotinate (151 mg, 1 mmol), acetic anydride(541 mg, 5.3 mmol) and acetic acid (52 mg, 0.87 mmol) was added3-(hydroxybenzyl)benzaldehyde (201 mg, 1.01 mmol). The reaction washeated to 120° C. for 24 hours and was then cooled to room temperaturebefore ethyl acetate (5 ml) and water (5 ml) were added. The biphasicmixture was separated and the organic phase was washed with an aqueoussaturated solution of sodium bicarbonate (5 ml). The organic phase wasthen filtered through magnesium sulfate absorbed onto silica gel and wasconcentrated in vacuo. The crude product was chromatographed onKieselgel 60, eluting with a gradient of 10–40% ethyl acetate iniso-hexane to give the product as a white solid (162 mg, 49% yield); MS[M+H]·332.The product from the previous step (162 mg) was dissolved in a mixtureof THF (2.5 ml) and 1 M aqueous NaOH solution (1.25 ml) and was thenheated for 2 hours at 60° C. The reaction was allowed to cool to roomtemperature overnight and was the reduced in vacuo to remove the THF. 1N aqueous HCl was added to precipitate out6-(E-3-phenoxy-phenyl]-vinyl)-nicotinic acid which was isolated byfiltration as a white solid (117 mg, 76% yield); H¹ NMR δ (d⁶-DMSO)6.95–7.85 (12 H, m), 8.25 (1 H, dd), 9.05 (1 H, d) 13.30 (1 H, br, s);MS [M+H]·318.

EXAMPLE B Scheme 2: Preparation Of6-(E-2-[-2-(4-isopropylbenzyloxy)-5-methylsulfanyl-phenyl]-vinyl-nicotinicAcid

Sodium hydride (160 mg, 60% w/w in mineral oil, 4 mmol) was added to asolution containing 4-isopropylbenzyl chloride (350 μL, 2.1 mmol) and6-[E-2-(-2-hydroxy-5-methylsulfanylphenyl)-vinyl]-nicotinic acid, methylester (600 mg, 2 mmol) in DMF (20 mL). The mixture was stirred overnightat room temperature. The reaction mixture was concentrated in vacuo andthe residue was dissolved in THF (10 mL). Methanol (4 mL) and aqueoussodium hydroxide (4 mL, 1 M) were added the solution was stirred at roomtemperature for 5 hours. The reaction mixture was concentrated in vacuobefore being dissolved in water (10 mL). This solution was acidifiedwith hydrochloric acid (1 M) and the resulting precipitate was isolatedby filtration, washed with water and dried in vacuo. The product wasobtained as a yellow solid (880 mg, quant.) δ_(H) (300 MHz, DMSO-d₆)13.2 (1 H, s), 9.01 (1 H, d), 8.22 (1 H, dd), 8.04 (1 H, d), 7.66 (1 H,d), 7.53 (1 H, d), 7.45 (1 H, d), 7.39 (2 H, d), 7.29−7.20 (3 H, m),7.11 (1 H, d), 5.18 (4 H, s), 2,87 (1 H, septet), 2.51 (3 H and residualDMSO-d₅, s), and 1.19 (6 H, d); m/z (LCMS) (ESI+) 420 (MH+); (ESI—) 418(M—H).

EXAMPLE C Scheme 2: Preparation of6-[E-2-(-2-hydroxy-5-methylsulfanylphenyl)-vinyl]-nicotinic Acid, MethylEster

Sodium methoxide (2.29 g, 42.4 mmol) was added to a suspension of6-[E-2-(-2-acetoxy-5-methylsulfanylphenyl)-vinyl]-nicotinic acid, methylester (13.26 g, 38.55 mmol) in methanol (200 mL). The mixture was heatedat 60° C. for 3 hours. The reaction mixture was concentrated in vacuoand water was added followed by enough hydrochloric acid (1 M) toacidify the solution. The resultant precipitate was isolated byfiltration, washed with water and dried in vacuo. This procedureafforded the product as a yellow solid (8.8 g, 76%) m/z (LCMS) (ESI+)302 (MH+); (ESI−) 300 (M—H).

EXAMPLE D Scheme 2: Preparation of6-[E-2-(-2-acetoxy-5-methylsulfanylphenyl)-vinyl]-nicotinic Acid, MethylEster

2-hydroxy-5-methylsulfanylbenzaldehyde (5.05 g, 30 mmol) was dissolvedin acetic anhydride (8 mL). Methyl 6-methylnicotinate (4.54 g, 30 mmol)and acetic acid (1.7 mL, 30 mmol) were added. The mixture was heated to120° C. and stirred for 18 hours. The mixture was allowed to cool toroom temperature before being poured into water (200 mL). The aqueousmixture was extracted with ethyl acetate (200 mL). The extract waswashed with brine, dried over magnesium sulfate and concentrated invacuo to afford a brown solid. This material was triturated with ethanolto give 6-[E-2-(-2-acetoxy-5-methylsulfanylphenyl)-vinyl]-nicotinicacid, methyl ester as a colourless solid (7.33 g, 71%) δ_(H) (300 MHz,DMSO-d₆) 9.06 (1 H, d), 8.28 (1 H, dd), 7.77−7.68 (3 H, m), 7.50 (1 H,d), 7.27 (1 H, d), 7.15 (1 H, d), 3.86 (3 H, s), 2.55 (3 H, s), and 2.36(3 H, s); m/z (ESI+) 344 (MH+).

EXAMPLE E Scheme 3: Preparation of

Compound (a) (260 mg 0.69 mm) was stirred with potassium carbonate (286mg 2.07 mm), potassium iodide (catalytic) and 2-methylbenzyl bromide(0.101 ml 0.76 mm) in dimethylformamide at 60° C. overnight.

Water (5 ml) was added to the cooled reaction and the mixture wasfiltered, washed well with water and dried under vacuum at roomtemperature. The compound was purified by bond elute chromatography,eluting with 20% ethyl acetate/isohexane. The product from this columnwas stirred with 2 N sodium hydroxide (1.725 ml 3.45 mm) intetrahydrofuran (4 ml) methyl alcohol (2 ml) and water (2 ml) for 3hours at room temperature. The mixture was then evaporated to dryness,diluted with water and acidified with 2 N hydrochloric acid to give aprecipitate. The precipitate was filtered off, washed well with waterand dried at room temperature under vacuum to give the product. (270 mg,83.4%) Nmr dmso-d₆ (d) 2.34 (3 H, s), 5.11–5.23 (4 H d) 6.72 (1 H s)7.05 (2 H s) 7.15–7.35 (5 H m) 7.4–7.5 (3 H m) 7.55–7.65 (2 H m)7.68–7.78 (1 H d) 8.18–8.23 (1 H d) 9.03 (1 H s) M.S.—MH⁺ 470.

EXAMPLE F Scheme 3: Preparation of

Compound (b) (9.65 g 35.61 mm) was stirred with 2-fluorobenzyl bromide(4.29 ml 35.61 mm), potassium carbonate (14.74 g 106.83 mm) potassiumiodide (1.0 g 6 mm catalytic) in dimethylformamide (40 ml).

After cooling, the mixture was poured into water and extracted intoethyl acetate. The combined organic extracts were dried over magnesiumsulphate, filtered and evaporated to give the crude product.Chromatography on silica using 0.6% methanol/methylene chloride,followed by 10% methanol/methylene chloride gave the pure product (1.89g 14%). M.S. MH⁺ 380.

EXAMPLE G Scheme 3: Preparation of

The diacetyl derivitive (15.36 g 43 mm) of the structure above wasstirred at room temperature with 4 N sodium methoxide (9.8 ml 43 mm) intetrahydrofuran (10 ml) and methanol (10 ml) for 1 hour. The mixture wasevaporated diluted with water and acidified with hydrochloric acid. Theresulting precipitate was filtered off washed with water and vacuumdried at 50° C. to give the product (11.2 g 96.1%) MS MH⁺ 272

EXAMPLE H Scheme 3: Preparation of

3,5-Dihydroxybenzaldehyde (10 g 72.46 mm) was stirred with 6-methylmethyl nicotinate (10.94 g 72.46 mm) in acetic acid (3.7 ml 65 mm) andacetic anydride (37 ml 0.39 m) at 120° C. overnight. On cooling thebrown solid mixture was diluted with ethyl acetate. The insolublematerial was filtered off and washed with ethyl acetate to give theproduct (15.36 g) The remaining organic solubles were washed with waterand then added to sodium bicarbonate and the solid filtered off washedwith water and vacuum dried(1.78 g). Both the solids were identical andso were combined to give the final product (17.14 g 66.6%) MS MH⁺356.

EXAMPLE I Scheme 4: Preparation of6-(E-2-[-2-(2-benzyloxy)-5-methylsulfanyl-phenyl]-vinyl)-nicotinic Acid,Methyl Sulphonamide

To a suspension of Compound (c) (100 mg) in dichloromethane (10 ml) wasadded methanesulfonamide (38 mg), 4-dimethylaminopyridine (130 mg), then1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (102 mg).The mixture was stirred for 20 hours at ambient temperature. Dilutedwith dichloromethane (20 ml), washed with 2 M hydrochloric acid (10 ml),brine (15 ml), and dried over Magnesium sulfate. Volatile material wasremoved by evaporation to give the title product (112 mg), as a solid.¹HNMR (CLCl₃) 2.48 (s, 3 H), 3.43 (s, 3 H), 5.20 (s, 2 H), 6.92 (d, 1H), 7.25 (m, 1 H+CDCl₃), 7.33–7.48 (m, 7 H), 7.57 (d, 1 H), 7.60 (s, 1H), 8.13 (d, 1 H), 8.32 (d, 1 H), 9.26 (s, 1 H), MS ES⁺ 455.13 (M+H)⁺.

EXAMPLE J

By analagous methods to those described compounds J₁₋₁₂₇ listed in Table1 were also made. Table 2 gives the parent molecular weight, mass specdata and the synthetic scheme for the compounds listed in Table 1.

In compounds 1–114 R³ is OH; in compound 115–123 R³ is methoxy; incompound 124 R³ is methylsulphonylamino; in compounds 125 R³ ismethoxyamino; in compounds 126–127 R³ is 2-hydroxyethylamide.

Compound 2 corresponds to the product of Example A. Compound 36corresponds to the product of Example B. Compound 101 corresponds toExample E. Compound 124 corresponds to the product of Example I.

TABLE 1 Compound number 2 3 4 5 1 H Methylthio H H 2 H Phenoxy H H 3 HCF₃ H CF3 4 H Benxyloxy H H 5 OH Br H Br 6 4-ChloroPhenylthio H H NO2 74-MethylPhenylthio H H NO2 8 Chloro H H Ethoxy 9 Chloro H H Chloro 10Chloro H H CF3 11 H H (5-t-Butyl)-thiazol-2-yl H 12 H(4-t-Butyl)-Phenoxy H H 13 Bromo H H OMe 14 Bromo H H OEt 151-morpholino H H NO2 16 3-Trifluoromethyl- H H NO2 phenoxy 17 methoxy HH SMe 18 4-Fluorobenzyloxy H H SMe 19 4-Methoxybenzyloxy H H SMe 20 OH HH SMe 21 OH H H OMe 22 Allyloxy H H SMe 23 Cyclopropyl H H SMe methoxy24 O-3-Pentyl H H SMe 25 benzyloxy H H OMe 26 Benzyloxy H H SMe 27 H4-Fluorophenyl H H 28 H 4-Chlorophenoxy H H 29 H OMe H OMe 30 H4-Methoxyphenoxy H H 31 Fluoro H H Trifluoromethyl 32 4-ChloroPhenylthioH H H 33 3-Carboxybenzyloxy H H SMe 34 4-Carboxybenzyloxy H H SMe 353-Nitrobenzyloxy H H SMe 36 4-Isopropylbenzyloxy H H SMe 374-Methylsulphonyl- H H SMe benzyloxy 38 3,5-Difluorobenzyloxy H H SMe 394-Vinylbenzyloxy H H SMe 40 2,4-Difluorobenzyloxy H H SMe 413-Trifluoromethyl- H H SMe 4-fluorobenzyloxy 42 3-Trifluoromethyl- H HSMe benzyloxy 43 3,4-Methylenedioxy- H H SMe benzyloxy 443-Fluorobenzyloxy H H SMe 45 2-Methylbenzyloxy H H SMe 463-Methylbenzyloxy H H SMe 47 2-Fluorobenzyloxy H H SMe 484-Bromobenzyloxy H H SMe 49 4-Methylbenzyloxy H H SMe 503-Methoxybenzyloxy H H SMe 51 3,4-Difluorobenzyloxy H H SMe 523-Carboxybenzyloxy H H H 53 3,5-Difluorobenzyloxy H H H 542-Cyanoobenzyloxy H H H 55 2-Methylbenzyloxy H H H 562,4-Difluorobenzyloxy H H H 57 3-Trifluoromethyl- H H H benzyloxy 582,5-Difluorobenzyloxy H H H 59 3,4-Methylenedioxy- H H H benzyloxy 603-Fluorobenzyloxy H H H 61 2-Fluorobenzyloxy H H H 62 4-FluorobenzyloxyH H H 63 3-Methoxybenzyloxy H H H 64 3-Phenylallyloxy H H SMe 653-Phenylpropoxy H H SMe 66 Cyclohexylmethoxy H H SMe 672-N-Methylpyrrolidino- H H SMe 2-Ethoxy 68 2-(4-Bromophenoxy)- H H SMeethoxy 69 2-Hydroxy-2- H H SMe Trifluoromethyl- ethoxy 70 4-(3,5- H HSMe dimethylisoxozolo)- methoxy 71 2-(2-1,3-diazolo)- H H SMe ethoxy 722-Carboxyfurano- H H SMe methoxy 73 H 2-Chlorobenzyloxy H H 74 BenzyloxyH H 2-Methoxyethoxy 75 2-Methylbenzyloxy H H 2-Methoxyethoxy 76Benzyloxy H H Trifluoromethoxy 77 3-Methylbenzyloxy H H Trifluoromethoxy78 Hydroxy H H t-Butyl 79 3-(5-methyl)isoxazolo- H H SMe methoxy 802-Furanomethoxy H H SMe 81 3-Pyridomethoxy H H SMe 82 2-ThiophenomethoxyH H SMe 83 3-Thiophenomethoxy H H SMe 84 Benzyloxy H H 2-Cyanobenzyloxy85 4-Phenylcarbamoyl- H H SMe benzyloxy 86 4-Carbamoylbenzyloxy H H SMe87 4-benzoylbenzyloxy H H SMe 88 4-Sulphamoyl- H H SMe benzyloxy 894-Carboxymethyl- H H SMe benzyloxy 90 4-(2-Methylcarboxy)- H H SMephenylbenzyloxy 91 4-Carboxymethoxy- H H SMe benzyloxy 924-Cyanobenzyloxy H H SMe 93 4-Nitrobenzyloxy H H SMe 94 H2-Cyanobenzyloxy H 2-Cyanobenzyloxy 95 H 2-Fluorobenzyloxy H2-Fluorobenzyloxy 96 H 2-Chlorobenzyloxy H 2-Chlorobenzyloxy 97 H3-(5-methyl)isoxazolyl- H 3-(5-methyl)- methoxy isoxazolylmethoxy 98 H2-[2-methylthiazol-4-yl] H 2-[4-(2-methyl)- ethoxy thiazolyl]-ethoxy 99H Benzyloxy H 2-Fluorobenzyloxy 100 H 2-chlorobenzyloxy H2-Fluorobenzyloxy 101 H 2-Methylbenzyloxy H 2-Fluorobenzyloxy 102 H2-Cyanobenzyloxy H 2-Fluorobenzyloxy 103 H 2-Trifluoromethyl- H2-Fluorobenzyloxy benzyloxy 104 H 2-Trifluoromethoxy-benzyloxy H2-Fluorobenzyloxy 105 H 2-Methoxybenzyloxy H 2-Fluorobenzyloxy 106 H2-[2-methylthiazol-4-yl] H Isopropoxy ethoxy 107 H 2-[2- H2-Pyridylmethoxy methylthiazol-4-yl]ethoxy 108 H 5-methylisoxazol-3-yl-H Isopropoxy methoxy 109 H 5-methylisoxazol-3-yl- H 2-Methylbenzyloxymethoxy 110 H 5-methylisoxazol-3-yl- H 4-(2-methyl)- methoxythiazolylmethoxy 111 H 2-[4-methylthiazol-5-yl] H 2-Methylbenzyloxyethoxy 112 H 2-[4- H 3-(5-methyl)- methylthiazol-5-yl]-isoxazolylmethoxy ethoxy 113 4-Isopropylbenzyloxy H H Methylsulphoxy 114Benzyloxy H H Methylsulphonyl 115 Ethylthio Methoxy H H 116 Hydroxy H HMethylthio 117 H 2-chlorobenzyloxy H H 118 H 2-[4- H Isopropoxymethylthiazol-5-yl]- ethoxy 119 H 2-[4- H 2-Pyridylmethoxymethylthiazol-5-yl]- ethoxy 120 H 5-methylisoxazol-3-yl- H Isopropoxymethoxy 121 H 5-methylisoxazol-3-yl- H 2-Methylbenzyloxy methoxy 122 H5-methylisoxazol-3-yl- H 2-[4-(2-methyl)- methoxy thiazolyl]-ethoxy 123H 2-[4- H 2-Methylbenzyloxy methylthiazol-5-yl]-ethoxy 124 Benzyloxy H HMethylthio 125 Benzyloxy H H Methylthio 126 Benzyloxy H H Bromo 127Benzyloxy H H Methylthio

TABLE 2 Parent Compound Molecular Mass Spec Synthetic Number Weight(+ve/−ve) scheme 1 271.34 272, 1 2 317.35 318, 1 3 361.25 362, 1 4331.37 332, 1 5 399.04 398, 400, 402, 1 6 412.85 411, 413 1 7 392.44391, 393 1 8 303.75 302, 304 1 9 294.14 295, 293 1 10 327.69 326, 328 111 364.47 365, 363 1 12 373.46 374, 372 1 13 334.17 334, 336 1 14 348.2348, 350 1 15 355.35 354, 356 1 16 430.34 431, 1 17 301.37 302, 300 2 18395.46 396, 394 2 19 407.49 408, 406 2 20 287.34 288, 286 2 21 271.28272, 270 2 22 327.41 328, 2 23 341.43 342, 2 24 357.48 358, 2 25 361.4362, 360 2 26 377.47 378, 376 2 27 319.34 320, 318 2 28 351.79 352, 3502 29 285.3 286, 284 2 30 347.37 348, 346 2 31 311.24 312, 310 2 32367.86 368, 366 2 33 421.48 422, 2 34 421.48 422, 420 2 35 422.46 423,421 2 36 419.55 420, 418 2 37 455.56 456, 454 2 38 413.45 414, 412 2 39403.5 404, 402 2 40 413.45 414, 412 2 41 463.45 464, 462 2 42 445.46446, 444 2 43 421.48 422, 420 2 44 395.46 396, 394 2 45 391.49 392, 3902 46 391.49 392, 390 2 47 395.46 396, 394 2 48 456.36 456, 458, 454, 4562 49 391.49 392, 390 2 50 407.49 408, 406 2 51 413.45 414, 412 2 52375.38 376, 374 2 53 367.36 368, 366 2 54 356.38 357, 355 2 55 345.4346, 344 2 56 367.36 368, 366 2 57 399.37 400, 398 2 58 367.36 368, 3662 59 375.38 376, 374 2 60 349.36 350, 348 2 61 349.36 350, 348 2 62349.36 350, 348 2 63 361.4 362, 360 2 64 403.5 404, 402 2 65 405.52 406,404 2 66 383.51 384, 382 2 67 398.53 399, 397 2 68 486.39 486, 488, 484,486 2 69 399.39 400, 398 2 70 396.47 397, 395 2 71 387.46 388, 386 2 72411.44 412, 410 2 73 365.82 366, 2 74 405.45 406 2 75 419.48 420 2 76415.37 416 2 77 429.4 430 2 78 297.36 298, 296 2 79 382.44 383, 2 80367.43 368, 2 81 378.45 379, 2 82 383.49 384, 2 83 383.49 384, 2 84462.51 463 2 85 496.59 497 2 86 420.49 421 2 87 481.57 482 2 88 456.54457 2 89 435.5 436 2 90 511.6 512 2 91 451.5 452 2 92 402.48 403 2 93422.46 423 2 94 487.52 488 2 95 473.48 474, 2 96 506.39 506, 2 97 447.45448, 446 2 98 507.63 508, 2 99 455.49 456, 454 3 100 489.94 490, 492,488, 490 3 101 469.52 470, 68 3 102 480.5 481, 479 3 103 523.49 524, 5223 104 539.49 540, 538 3 105 485.52 486, 484 3 106 424.52 425, 423 3 107473.55 474, 472 3 108 394.43 395, 393 3 109 456.5 457, 455 3 110 463.52464, 462 3 111 486.59 487, 485 3 112 477.54 478, 476 3 113 435.55 434,436 5 114 409.464 , 408 5 115 329.42 330, 1 116 301.37 302, 300 2 117379.85 380, 2 118 438.55 439, 3 119 487.58 488, 3 120 408.46 409, 3 121470.53 471, 469 3 122 477.54 478, 476 3 123 500.62 501, 499 3 124 454.57455.13 4 125 406.51 407.12 4 126 453.339 453, 4 127 420.534 421, 4

EXAMPLE K Scheme 5: Preparation of6-(E-2-[-2-(2-benzyloxy)-5-methylsulfanyl-phenyl]-vinyl)-nicotinic Acid,N-methoxyamide,

To a stirred suspension of6-{(E)-2-[2-(benzyloxy)-5-(methylthio)phenyl]ethenyl}nicotinic acid (82mg, 0.22 mmol) in DCM (10 ml) was added oxalyl chloride (35 mg, 0.28mmol) and DMF (catalytic amount). The mixture was stirred at ambienttemperature for 17 hours, and volatile material removed by evaporationto give a gum which was then suspended in DCM (10 ml). Methoxyaminehydrochloride (37 mg, 0.44 mmol) and triethylamine (0.06 ml, 0.43 mmol)were added to the suspension and the resulting solution stirred atambient temperature for 4 hours. It was then diluted with DCM (20 ml)and washed sequentially with 2 M hydrochloric acid (20 ml), brine (20ml), and dried over MgSO₄. Volatile material was removed by evaporationto leave a gum which was purified by flash chromatography on silica,eluting with 1–2% methanol in DCM to give an oil. Triturated withdiethyl ether gave6-(E-2-[-2-(2-benzyloxy)-5-methylsulfanyl-phenyl]-vinyl)-nicotinic acid,N-methoxyamide (33 mg) as a solid, NMR: δ_(H) (300 MHZ, DMSO-d₆) 2.48(s, 3 H+DMSO), 3.72 (s, 3 H), 5.22 (s, 2 H), 7.11 (d, 1 H), 7.24 (s, 1H), 7.30–7.53 (m, 7 H), 7.68 (s, 1 H), 8.05 (m, 2 H), 8.88 (s, 1 H),11.82 (s, 1 H); m/z 407 (M+H)⁺.

EXAMPLE L Scheme 6: Preparation of6-(E-2-[-2-(3,5-dibenzyloxy)-phenyl]-vinyl)-pyridine-3-oxyacetic acid.

To a stirred solution of6-(E-2-[-2-(3,5-dibenzyloxy)-phenyl]-vinyl)-pyridine-3-oxyacetic acidt-butyl ester (100 mg, 0.19 mmol) in dichloromethane (2 ml) was addedtrifluoroacetic acid (1 ml). The solution was stirred at ambienttemperature for 6 hours. Volatile material was removed by evaporation,and the residue azeotroped with toluene to give an oil. This wastriturated under diethyl ether to give the title compound (72 mg) as asolid, NMR: δ_(H) (300 MHz, DMSO-d₆) 4.80 (s, 2 H), 5.12 (s, 4 H), 6.60(s, 1 H), 6.89 (s, 2 H), 7.08–7.60 (m, 14 H), 8.31 (s, 1 H), m/z 468(M+H)⁺.The requisite t-butyl ester starting material was prepared as follows:

To a suspension of 3-hydroxy-6-(E-2-[-2-(3,5-dibenzyloxy)-phenyl]-vinyl)pyridine (150 mg) in anhydrous THF (10 ml) was added sodium hydride (30mg) at ambient temperature, under an atmosphere of nitrogen. Thereaction was allowed to stir for 20 minutes and then t-butyl bromoacetate (0.06 ml) was added. The reaction was stirred for 30 minutesbefore being cooled to 0° C. and DMF (3 ml) added. The reaction was thenallowed to warm ambient temperature, when water (20 ml) was added. Theaqueous was extracted with ethyl acetate (3×20 ml) and the extractscombined, dried (MgSO₄) and evaporated to leave an oil. This waspurified by flash chromatography on a 10 g silica Bondelut, to give anoil which was triturated under diethyl ether:hexane (1:1) to give6-(E-2-[-2-(3,5-dibenzyloxy)-phenyl]-vinyl)-pyridine-3-oxyacetic acidt-butyl ester (135 mg) as a solid, MS m/z 524 (M+H)⁺.The requisite 3-hydroxy pyridine starting material was prepared asfollows:

To a suspension of 3-acetoxy-6-(E-2-[-2-(3,5-dibenzyloxy)-phenyl]-vinylpyridine (100 mg) in methanol (2 ml) was added sodium hydroxide (0.44ml, 0.86 mmol), and the mixture stirred at ambient temperature for 1.5hours. An excess of 2 M hydrochloric acid was added. A precipitateformed, which was filtered off, washed sequentially with water andether, and dried under vacuum at 60° C. for 5 hours, to give3-hydroxy-6-(E-2-[-2-(3,5-dibenzyloxy)-phenyl]-vinyl) pyridine (82 mg)as a solid, m/z 410 (M+H)⁺.The requisite 3-acetoxy pyridine starting material was prepared asfollows:

To a stirred solution of6-{2-[3,5-bis(benzyloxy)phenyl]-2-hydroxyethyl}pyridin-3-ol (105 mg) inacetic anhydride (0.23 ml) was added acetic acid (0.23 ml); the mixturewas heated to 120° C. and stirred for 17 hours. It was then allowed tocool to ambient temperature and water (10 ml) was added, followed byextraction with ethyl acetate (3×30 ml). The extracts were combined,dried (MgSO₄) and evaporated to give an oil, which was triturated underhexane to give the title compound (80 mg) as a solid. MS ES⁺ 452 (M+H)⁺.The requisite6-{2-[3,5-bis(benzyloxy)phenyl]-2-hydroxyethyl}pyridin-3-ol startingmaterial was prepared as follows:

To a stirred solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpyridine (1.20 g) in anhydrous THF (15 ml) under nitrogen and at −78° C.was added LDA (3.22 ml), and the solution stirred at −78° C. for 1 hour.3,5 dibenzyloxy-benzaldehyde (2.05 g) was then added dropwise as asolution in THF, and the reaction mixture allowed to warm to ambienttemperature over 1 hour. Water (20 ml) was added and the resultingmixture extracted with ethyl acetate (3×30 ml). The extracts werecombined, washed with brine (20 ml), dried (MgSO₄) and evaporated togive a gum. This was dissolved in THF (10 ml) and concentratedhydrochloric acid (10 ml) added. The mixture was stirred at ambienttemperature for 3 hours, cooled to 0° C. and taken to pH 8.5 withconcentrated ammonia solution. The mixture was diluted with water (50ml) and extracted with ethyl acetate (3×100 ml). The extracts werecombined, dried (MgSO₄) and evaporated to leave an oil which waspurified by MPLC on silica, eluting with 60–100% ethyl acetate in hexaneto give 6-{2-[3,5-bis(benzyloxy)phenyl]-2-hydroxyethyl}pyridin-3-ol(2.25 g) as a glass, m/z 428 (M+H)⁺.

EXAMPLE M Scheme 7: Preparation of E2-{-2-[3,5-di-(2-chlorobenzyloxy)]-phenyl}-vinyl-thiazole-4-carboxylicAcid

This was prepared from E2-{-2-[3,5-di-(2-chlorobenzyloxy)]-phenyl}-vinyl-thiazole-4-carboxylicacid ethyl ester by alkaline hydrolysis in a manner similar to thatdescribed in Example A, Scheme 1.The requisite ethyl ester starting material was prepared as follows:

Ethyl 2-[(diethoxyphophoryl)methyl]-1,3-thiazole-4-carboxylate (280 mgs,0.91 mmol) in dry tetrahydrofuran (10 ml) was added to a stirredsuspension of sodium hydride (40 mgs of 60% dispersion, 1 mmol) in drytetrahydrofuran (10 ml). After stirring for half an hour at roomtemperature a solution of 3,5 bis (2-chlorobenzyl)benazaldehyde (420 mgs1.09 mmol) in dry tetrahydrofuran (10 ml) was added slowly. The mixturewas stirred at ambient temperature for 4 hours, quenched with water andacidified with 2 M aq hydrochloric acid. The mixture was extracted withethyl acetate and the extrac combined, dried (MgSO₄) and evaporated toleave a gum. Chromatography on silica, eluting with 20% EtOAc in hexane,gave E2-{-2-[3,5-di-(2-chlorobenzyloxy)]-phenyl}-vinyl-thiazole-4-carboxylicacid ethyl ester (260 mgs), NMR δ_(H) (300 MHz, DMSO-d₆); 1.25–1.35 (3H,t); 4.25–4.35 (2 H, q); 5.2 (4 H, s); 6.69 (1 H, s); 7.08 (2 H,s);7.34–7.45 (4 H, m); 7.45–7.55 (3 H,m); 7.55–7.65 (3 H,m); 8.45 (1 H, m).The requisite ethyl2-[(diethoxyphophoryl)methyl]-1,3-thiazole-4-carboxylate startingmaterial was prepared as follows:

Ethyl 2-(bromomethyl)-1,3-thiazole-5-carboxylate (460 mgs, 1.85 mmol) indry tetrahydrofuran (2.5 ml) was added dropwise to triethylphosphite(2.5 ml, 2.46 g, 14.8 mmol) under argon at a temperature of 105° C. Oncompletion of the addition the mixture was warmed to 140° C. at which itwas maintained for one hour. The triethylphosphite was then removedunder reduced pressure and the resultant material chromatographed(silica, EtOAc/hexane) to give ethyl2-[(diethoxyphophoryl)methyl]-1,3-thiazole-4-carboxylate (300 mgs), NMR:δ_(H) (300 MHz, DMSO-d₆): 1,15–1.35 (9 H, m); 3.95–4.12 (4 H, m);4.22–4.35 (2 H,q); 8.43 (1 H,s).The requisite ethyl 2-(bromomethyl)-1,3-thiazole-5-carboxylate startingmaterial was prepared as follows:

N-Bromosuccinimide (0.91 g, 5.1 mmol) was added to a solution of ethyl2-methyl-thiazole-5-carboxylate (0.8 g, 4.7 mmol) in carbontetrachloride. The resultant reaction mixture was stirred for one hourwhilist being illuminated by a photoflood lamp. After removing thesolvent from the reaction mixture the resultant material was partitionedbetween ethyl acetate and water. The organic phase was then separatedoff, dried (MgSO₄) and the evaporated. Chromatography on silica, elutingwith 30% ethyl acetate in hexane, gave ethyl2-(bromomethyl)-1,3-thiazole-5-carboxylate (490 mgs), NMR: δ_(H) (300MHz, DMSO-d₆, 1.20–1.38 (3 H,t); 4.20–4.37 (2 H,q); 5.05 (2 H, s); 8.55(1 H, s).

EXAMPLE N

By analogous methods to those described compounds N₁₋₈ in Table 3 werealso made.

TABLE 2 Route No Structure (Example) MS NMR 1

I 455 δ_(H)(300MHz, CDCl₃) 2.48(s, 3H), 3.43 (s, 3H), 5.20(s, 2H), 6.92(d, 1H), 7.25(s, CHCl₃+1H), 7.33–7.48(m, 7H), 7.57 (d, 1H), 7.60(s, 1H),8.13 (d, 1H), 8.32(d, 1H), 9.26 (s, 1H). E FORM 2

K Scheme 5 407 δ_(H)(300MHz, DMSO-d₆)2.48 (s, 3H+DMSO), 3.72(s, 3H),5.22 (s, 2H), 7.11(d, 1H), 7.24 (s, 1H), 7.30–7.53 (m, 7H), 7.68 (s,1H),8.05 (m, 2H), 8.88 (s, 1H),11.82 (s, 1H). E FORM 3

A Scheme 1 373 δ_(H)(300MHz, DMSO-d₆)1.2 (s, 9H), 7.0 (d, 3H), 7.4(m,6H), 7.8 (d, 1H), 8.7(s,1H), 9.1 (s,1H). E FORM 4

L Scheme 6 468 δ_(H)(300MHz, DMSO-d₆)4.80 (s, 2H), 5.12 (s, 4H),6.60 (s,1H), 6.89 (s, 2H),7.08–7.60 (m, 14H), 8.31(s, 1H). E FORM 5

AScheme 1* δ_(H)(300MHz, DMSO-d₆)5.21 (4H, s), 6.72 (1H, s),7.10 (2H,app s), 7.30–7.44 (5H, m), 7.44–7.55(2H, m), 7.55–7.65 (2, m),7.90–8.1(1H, d), 9.14(2H, s). E FORM 6

M Scheme 7(by analogywithExample 8) δ_(H)(300MHz, DMSO-d₆)5.20 (4H, s),6.62 (1H, s),6.71 (1H, d), 6.97 (2H, d),7.14 (1H, d), 7.26 (2H, m),7.40(4H, m), 7.52 (2H,m), 7.63 (2H, m). E FORM 7

M Scheme 7(by analogywithExample 8) 512514 δ_(H)(300MHz, DMSO-d₆),5.19(4H, s), 6.68 (1H, s),7.01 (2H, s), 7.31–7.45 (5,m), 7.45–7.58 (~2.5H,m),7.58–7.69 (~2.5H, m), 7.87(1H, s) E FORM 8

M Scheme 7**(described) 512 δ_(H)(300MHz, DMSO-d₆),5.19 (4H, s), 6.72(1H, s),7.08 (2H, s), 7.30–7.45(4H, m), 7.45–7.55 (2H,m), 7.55–7.68 (4H,m),8.33 (1H, s) *Example 5 - starting material (ethyl 2-methylpyrimidine-5-carboxylate) prepared according to J Het Chem 27 295(1990). **Ethyl 2 methyl-1,3-thiazole-5-carboxylate prepared asdescribed in J. Am. Chem. Soc. 1982, 104, 4461–4465The compounds A–I, J₁₋₁₂₇, K, L, M and N₁₋₈ were found to have anactivity of at least 40% activity at 10 μm when tested in the GLK/GLKRPscintillation proximity assay described below.

BIOLOGICAL Tests

The biological effects of the compounds of the invention may be testedin the following way:

(1) Enzymatic activity of GLK may be measured by incubating GLK, ATP andglucose. The rate of product formulation may be determined by couplingthe assay to a G-6-P dehydrogenase, NADP/NADPH system and measuring theincrease in optical density at 340 nm (Matschinsky et al 1993).

(2) A GLK/GLKRP binding assay for measuring the binding interactionsbetween GLK and GLKRP. The method may be used to identify compoundswhich modulate GLK by modulating the interaction between GLK and GLKRP.GLKRP and GLK are incubated with an inhibitory concentration of F-6-P,optionally in the presence of test compound, and the extent ofinteraction between GLK and GLKRP is measured. Compounds which eitherdisplace F-6-P or in some other way reduce the GLK/GLKRP interactionwill be detected by a decrease in the amount of GLK/GLKRP complexformed. Compounds which promote F-6-P binding or in some other wayenhance the GLK/GLKRP interaction will be detected by an increase in theamount of GLK/GLKRP complex formed. A specific example of such a bindingassay is described below

GLK/GLKRP SCINTILLATION PROXIMITY ASSAY

Recombinant human GLK and GLKRP were used to develop a “mix and measure”96 well SPA (scintillation proximity assay). (A schematic representationof the assay is given in FIG. 3). GLK (Biotinylated) and GLKRP areincubated with streptavidin linked SPA beads (Amersham) in the presenceof an inhibitory concentration of radiolabelled [3H]F-6-P (AmershamCustom Synthesis TRQ8689), giving a signal as depicted in FIG. 3.Compounds which either displace the F-6-P or in some other way disruptthe GLK/GLKRP binding interaction will cause this signal to be lost.

Binding assays were performed at room temperature for 2 hours. Thereaction mixtures contained 50 mM Tris-HCl (pH=7.5) 2 mM ATP, 5 mMMgCl₂, 0.5 mM DTT, recombinant biotinylated GLK (0.1 mg), recombinantGLKRP (0.1 mg), 0.05 mCi [3H] F-6-P (Amersham) to give a final volume of100 ml. Following incubation, the extent of GLK/GLKRP complex formationwas determined by addition of 0.1 mg/well avidin linked SPA beads(Amersham) and scintillation counting on a Packard TopCount NXT.

The exemplified compounds described above were found to have an activityof at least 40% activity at 10 μm when tested in the GLK/GLKRPscintillation proximity assay.

(3) A F-6-P/GLKRP binding assay for measuring the binding interactionbetween GLKRP and F-6-P. This method may be used to provide furtherinformation on the mechanism of action of the compounds. Compoundsidentified in the GLK/GLKRP binding assay may modulate the interactionof GLK and GLKRP either by displacing F-6-P or by modifying theGLK/GLKRP interaction in some other way. For example, protein—proteininteractions are generally known to occur by interactions throughmultiple binding sites. It is thus possible that a compound whichmodifies the interaction between GLK and GLKRP could act by binding toone or more of several different binding sites.

The F-6-P/GLKRP binding assay identifies only those compounds whichmodulate the interaction of GLK and GLKRP by displacing F-6-P from itsbinding site on GLKRP.

GLKRP is incubated with test compound and an inhibitory concentration ofF-6-P, in the absence of GLK, and the extent of interaction betweenF-6-P and GLKRP is measured. Compounds which displace the binding ofF-6-P to GLKRP may be detected by a change in the amount of GLKRP/F-6-Pcomplex formed. A specific example of such a binding assay is describedbelow

F-6-P/GLKRP SCINTILLATION PROXIMITY ASSAY

Recombinant human GLKRP was used to develop a “mix and measure” 96 wellscintillation proximity assay. (A schematic representation of the assayis given in FIG. 4). FLAG-tagged GLKRP is incubated with protein Acoated SPA beads (Amersham) and an anti-FLAG antibody in the presence ofan inhibitory concentration of radiolabelled [3H]F-6-P. A signal isgenerated as depicted in FIG. 4. Compounds which displace the F-6-P willcause this signal to be lost. A combination of this assay and theGLK/GLKRP binding assay will allow the observer to identify compoundswhich disrupt the GLK/GLKRP binding interaction by displacing F-6-P.

Binding assays were performed at room temperature for 2 hours. Thereaction mixtures contained 50 mM Tris-HCl (pH=7.5), 2 mM, ATP, 5 mMMgCl₂, 0.5 mM DTT, recombinant FLAG tagged GLKRP (0.1 mg), Anti-Flag M2Antibody (0.2 mg) (IBI Kodak), 0.05 mCi [3H] F-6-P (Amersham) to give afinal volume of 100 ml. Following incubation, the extent of F-6-P(Amersham) complex formation was determined by addition of 0.1 mg/wellprotein A linked SPA beads (Amersham) and scintillation counting on aPackard TopCount NXT.

PRODUCTION OF RECOMBINANT GLK AND GLKRP Preparation of mRNA

Human liver total mRNA was prepared by polytron homogenisation in 4 Mguanidine isothiocyanate, 2.5 mM citrate, 0.5% Sarkosyl, 100 mMb-mercaptoethanol, followed by centrifugation through 5.7 M CsCl, 2.5 mMsodium acetate at 135,000 g (max) as described in Sambrook J, Fritsch EF & Maniatis T, 1989.

Poly A⁺ mRNA was prepared directly using a FastTrack™ mRNA isolation kit(Invitrogen).

PCR Amplification of GLK and GLKRP cDNA Sequences

Human GLK and GLKRP cDNA was obtained by PCR from human hepatic mRNAusing established techniques described in Sambrook Fritsch & Maniatis,1989. PCR primers were designed according to the GLK and GLKRP cDNAsequences shown in Tanizawa et al 1991 and Bonthron, D. T. et al 1994(later corrected in Warner, J. P. 1995).

CLONING IN BLUESCRIPT II VECTORS

GLK and GLKRP cDNA was cloned in E. coli using pBluescript II, (Short etal 1998) a recombinant cloning vector system similar to that employed byYanisch-Perron C et al (1985), comprising a colEI-based replicon bearinga polylinker DNA fragment containing multiple unique restriction sites,flanked by bacteriophage T3 and T7 promoter sequences; a filamentousphage origin of replication and an ampicillin drug resistance markergene.

TRANSFORMATIONS

E. Coli transformations were generally carried out by electroporation.400 ml cultures of strains DH5a or BL21 (DE3) were grown in L-broth toan OD 600 of 0.5 and harvested by centrifugation at 2,000 g. The cellswere washed twice in ice-cold deionised water, resuspended in 1 ml 10%glycerol and stored in aliquots at −70° C. Ligation mixes were desaltedusing Millipore V series™ membranes (0.0025 mm) pore size). 40 ml ofcells were incubated with 1 ml of ligation mix or plasmid DNA on ice for10 minutes in 0.2 cm electroporation cuvettes, and then pulsed using aGene Pulser™ apparatus (BioRad) at 0.5 kVcm⁻¹, 250 mF, 250 ?.Transformants were selected on L-agar supplemented with tetracyline at10 mg/ml or ampicillin at 100 mg/ml.

EXPRESSION

GLK was expressed from the vector pTB375NBSE in E. coli BL21 cells,producing a recombinant protein containing a 6-His tag immediatelyadjacent to the N-terminal methionine. Alternatively, another suitablevector is pET21(+)DNA, Novagen, Cat number 697703. The 6-His tag wasused to allow purification of the recombinant protein on a column packedwith nickel-nitrilotriacetic acid agarose purchased from Qiagen (cat no30250).

GLKRP was expressed from the vector pFLAG CTC (IBI Kodak) in E. coliBL21 cells, producing a recombinant protein containing a C-terminal FLAGtag. The protein was purified initially be DEAE Sepharose ion exchangefollowed by utilisation of the FLAG tag for final purification on an M2anti-FLAG immunoaffinity column purchased from Sigma-Aldrich (cat no.A1205).

BIOTINYLATION OF GLK

GLK was biotinylated by reaction with biotinamidocaproateN-hydroxysuccinimide ester (biotin-NHS) purchased from Sigma-Aldrich(cat no. B2643). Briefly, free amino groups of the target protein (GLK)are reacted with biotin-NHS at a defined molar ratio forming stableamide bonds resulting in a product containing covalently bound biotin.Excess, non-conjugated biotin-NHS is removed from the product bydialysis. Specifically, 7.5 mg of GLK was added to 0.31 mg of biotin-NHSin 4 mL of 25 mM HEPES pH=7.3, 0.15 M KCl, 1 mM dithiothreitol, 1 mMEDTA, 1 mM MgCl₂ (buffer A). This reaction mixture was dialysed against100 mL of buffer A containing a further 22 mg of biotin-NHS. After 4hours excess biotin-NHS was removed by extensive dialysis against bufferA.

PHARMACEUTICAL COMPOSITIONS

The following illustrative representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed“Compound X”), for therapeutic or prophylactic use in humans:

mg/tablet (a) Tablet I Compound X 100 Lactose Ph. Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II Compound X 50 Lactose Ph. Eur223.75 Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone(5% w/v paste) 2.25 Magnesium stearate 3.0 (c) Tablet III Compound X 1.0Lactose Ph. Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste (5%w/v paste) 0.75 Magnesium stearate 1.0 mg/capsule (d) Capsule Compound X10 Lactose Ph. Eur 488.5 Magnesium 1.5 (50 mg/ml) (e) Injection ICompound X 5.0% w/v 1 M Sodium hydroxide solution 15.0% v/v 0.1 MHydrochloric acid (to adjust pH = to 7.6) Polyethylene glycol 400 4.5%w/v Water for injection to 100% (10 mg/ml) (f) Injection II Compound X1.0% w/v Sodium phosphate BP 3.6% w/v 0.1 M Sodium hydroxide solution15.0% v/v Water for injection to 100% 1 mg/ml, buffered to pH = 6) (g)Injection III Compound X 0.1% w/v Sodium phosphate BP 2.26% w/v Citricacid 0.38% w/v Polyethylene glycol 400 3.5% w/v Water for injection to100% mg/ml (h) Aerosol I Compound X 10.0 Sorbitan trioleate 13.5Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0 (i) AerosolII Compound X 0.2 Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)Aerosol III Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (k) Aerosol IV Compound X 2.5 Soyalecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 ml (l) Ointment Compound X 40 mg Ethanol300 μl Water 300 μl 1-Dodecylazacycloheptan-2-one 50 μl Propylene glycolto 1 ml

NOTE

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)–(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate. The aerosol formulations (h)–(k) may beused in conjunction with standard, metered dose aerosol dispensers, andthe suspending agents sorbitan trioleate and soya lecithin may bereplaced by an alternative suspending agent such as sorbitan monooleate,sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleicacid.

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1. A compound of Formula (II) or a salt, solvate, or prodrug thereof

wherein A is pyridyl; R³ is selected from OH, —O-C₁₋₆alkyl, and NHR⁶;each R⁴ is independently from halo, —C_(3-a)F_(a), CN, NO₂, NH₂,C₁₋₆alkyl, —OC₁₋₆alkyl, —COOH, —C(O)OC₁₋₆alkyl, OH, phenyl optionallysubstituted with C₁₋₆alkyl, or —C(O)OC₁₋₆alkyl, and R⁵—X¹—; R⁵ isselected from hydrogen, C₁₋₆alkyl, —CH_(3-a)F_(a), phenyl, naphthyl,heterocyclyl, and C₃₋₇cycloalkyl; wherein R⁵ is optionally substitutedwith halo, C₁₋₆alkyl, —CH_(3-a)F_(a), CN, NO₂, NH₂, COOH, or—C(O)OC₁₋₆alkyl, and wherein each phenyl, naphthyl, or heterocyclyl ringin R⁵ is optionally substituted with halo, CH_(3-a)F_(a), CN, NO₂, NH₂,C₁₋₆alkyl, —OC₁₋₆alkyl, COOH, —C(O)OC₁₋₆alkyl, or OH; R⁶ is selectedfrom hydrogen, C₁₋₆alkyl, OC₁₋₆alkyl, SO₂C₁₋₆alkyl, and (CH₂)₀₋₃OH; eachX is a linker independently selected from —O—Z—, —O—Z—O—Z—, —OC(O)—Z—,—S—Z—, —SO—Z—, —SO₂—Z—, —SO₂N(R⁷)—Z—, and —S(O)₂N(R⁷)C(O)—Z—; each X¹ isa linker independently selected from —Z—, —O—Z—, —O—Z—O—Z—, —C(O)O—Z—,—OC(O)—Z—, —S—Z—, —SO—Z—, —SO₂—Z—, —N(R⁷)—Z—, —N(R⁷)SO₂—Z—,—SO₂N(R⁷)—Z—, —(CH₂)₁₋₄—, —CH═CH—Z—, —C≡C—Z—, —N(R⁷)CO—Z—,—C(O)N(R⁷)—Z—, —C(O)N(R⁷)S(O)₂—Z—, —S(O)₂N(R⁷)C(O)—Z—, —C(O)—Z—, and adirect bond; each R⁷ is independently selected from hydrogen, C₁₋₆alkyland —C₂₋₄alkyl-O-C₁₋₄alkyl; each Z is a direct bond; each Z¹ isindependently selected from a direct bond, C₂₋₆alkenylene and a group ofthe formula —(CH₂)_(p)—C(R⁶)₂—(CH₂)_(q)—; each a is independently 1, 2or 3; p is 0, 1 or 2; q is 0, 1 or 2; and p+q<4.
 2. A compound accordingto claim 1 or a salt, solvate, or prodrug thereof, wherein X isindependently selected from: —O—Z— or SO₂N(R⁷)—Z—; and Z¹ isindependently selected from a direct bond, —CH₂—, —(CH₂)₂— and


3. A pharmaceutical composition, comprising a compound according toclaim 1 or 2, or a salt, solvate, or prodrug thereof, together with apharmaceutically acceptable diluent or carrier.
 4. A method of treatingdiabetes, comprising administering to a patient a compound of claim 1 or2, or a salt, solvate, or prodrug thereof.
 5. A method of treatingobesity, comprising administering to a patient a compound of claim 1 or2, or a salt, solvate, or prodrug thereof.